Details of a Researcher - Ohtani, Hisakazu

Papers - Ohtani, Hisakazu

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The effect of organic solvents on the in vitro transport activity of three OATP isoforms

Saito R., Akiyoshi T., Tsujii K., Takahashi R., Kataoka H., Imaoka A., Ohtani H.

Toxicology in Vitro 107 106059 2025.08

ISSN 08872333

Purpose: In vitro studies of transporter activity often require the addition of organic solvents such as dimethyl sulfoxide (DMSO), methanol, and ethanol, to dissolve substrates and/or inhibitors. Although this may attenuate the transport activity, the influence of different types of organic solvents on transporter activity has not been elucidated. This study aimed to quantitatively assess the impact of organic solvents on the transport activity of organic anion transporting polypeptide (OATP) 1B1, 1A2, and 2B1. Methods: The concentration-dependent influence of DMSO, methanol, and ethanol on the uptake of [3H]estrone 3-sulfate mediated by OATP1A2, OATP2B1 or 2′,7′-dichlorofluorescein (DCF) mediated by OATP1B1 was assessed using HEK293 cells expressed the respective OATP protein and the concentration that reduced the uptake by 20 % (IC<inf>20</inf>) was calculated. Results and discussion: The uptake activities of OATPs were reduced by methanol and ethanol in a concentration-dependent manner, with IC<inf>20</inf> values of 2.4–3.4 % and 0.51–3.8 % respectively. In contrast, DMSO did not affect the OATP2B1-mediated uptake at the maximum concentration (10 %) of DMSO whereas it exhibited concentration-dependent inhibition for OATP1B1 and 1A2 with IC<inf>20</inf> values of approximately 3 % and 0.7 %, respectively. This study provides useful information regarding experimental conditions for evaluating OATPs activity in vitro.

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Comparative analysis of the single-molecule transport kinetics of OATP1B1 genetic variants

Tsujii K., Yajima K., Akiyoshi T., Sakamoto K., Suzuki Y., Oka T., Imaoka A., Yamamura H., Kurokawa J., Ohtani H.

Journal of Pharmacological Sciences 158 ( 3 ) 166 - 171 2025.07

ISSN 13478613

Several genetic variants of OATP1B1, a hepatic uptake transporter, increase the blood concentrations of substrate drugs, e.g., ∗15 carriers exhibit higher blood substrate concentrations than ∗1b carriers. It remains unclear whether these differences are due to changes in expression or intrinsic activity (transport activity per OATP1B1 molecule). This study compared the intrinsic activity of four OATP1B1 variants, ∗1a, ∗1b, ∗5, and ∗15, using HEK293 cell lines that co-expressed large-conductance Ca2+-activated K+ (BK) channels and one of the OATP1B1 variants. To estimate the kinetic parameters K<inf>m</inf> and V<inf>max</inf>, 2′, 7′-dichlorofluorescein uptake was evaluated. The number of OATP molecules per cell (Q<inf>T</inf>) was calculated from BK channel-mediated whole-cell conductance and the OATP1B1/BK channel expression ratio (ρ) (determined by LC-MS/MS). V<inf>max,int</inf> (maximum intrinsic transport velocity) was obtained by dividing V<inf>max</inf> by Q<inf>T</inf>, and intrinsic clearance (CL<inf>int</inf>) was calculated as V<inf>max,int</inf>/K<inf>m</inf>. The K<inf>m</inf> values of ∗1a, ∗1b, ∗5, and ∗15 were 12.5, 9.19, 7.53, and 10.4 μM, and their V<inf>max,int</inf> values were 3.0, 7.0, 1.5, and 1.2 × 10−21 mol/OATP molecule/min, respectively. Accordingly, the CL<inf>int</inf> value for OATP1B1∗15 was 15 % lower than that for OATP1B1∗1b, suggesting that the increased blood substrate concentrations observed in OATP1B1∗15 carriers may be due to the decreased intrinsic activity of OATP1B1∗15.

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Efficacy of De-Escalation to Cefmetazole in Patients with Bacteremic Urinary Tract Infections Caused by Extended-Spectrum β-Lactamase-Producing Escherichia coli

Namiki Takaya, Yokoyama Yuta, Kimura Motonori, Fukuda Shogo, Seyama Shoji, Iketani Osamu, Uwamino Yoshifumi, Jibiki Aya, Kawazoe Hitoshi, Ohtani Hisakazu, Hasegawa Naoki, Matsumoto Kazuaki, Oda Rentaro, Hashi Hideki, Suzuki Sayo, Nakamura Tomonori

Biological and Pharmaceutical Bulletin (The Pharmaceutical Society of Japan) 48 ( 5 ) 537 - 544 2025.05

ISSN 09186158

This study aimed to clarify the optimal value for the unbound cefmetazole concentration to remain above the minimum inhibitory concentration (MIC) (fT ≥ MIC) for efficacy of de-escalation to cefmetazole in patients with bacteremic urinary tract infection by extended-spectrum β-lactamase-producing Escherichia coli. This double-center retrospective observational study was conducted at Tokyo Bay Urayasu Ichikawa Medical Center and Keio University Hospital from January 2012 to October 2022. Efficacy was determined via clinical evaluation (mortality rate, recurrence rate, vital changes) and bacteriological evaluation, and the optimal fT ≥ MIC was calculated via receiver operating characteristic curve analysis. As a result, the number of patients evaluated were 40 (35 and 5 in the treatment success and treatment failure groups, respectively). Univariate analysis showed that fT ≥ MIC, recurrence rate, and MIC for cefmetazole against bacteria were significantly different for the two groups (p < 0.05). Receiver operating characteristic curve analysis showed that the optimal fT ≥ MIC indicating efficacy was 57% (area under the curve: 0.94, 95% confidence interval: 0.86–1.00, p = 0.002). All patients with fT ≥ MIC ≥ 57% had successful treatment, whereas the frequency of treatment failure was high among those with fT ≥ MIC <57%. The optimal fT ≥ MIC for the clinical efficacy of de-escalation to cefmetazole in patients with bacteremic urinary tract infection by extended-spectrum β-lactamase-producing E. coli was fT ≥ MIC ≥ 57%. This finding would be useful for optimal dosing of cefmetazole.

Current Use of Generative Artificial Intelligence in Pharmacy Practice: A Literature Mini-review

Kiyomiya Keisuke, Aomori Tohru, Kawazoe Hitoshi, Ohtani Hisakazu

Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences) (Japanese Society of Pharmaceutical Health Care and Sciences) 51 ( 4 ) 177 - 186 2025.04

ISSN 1346342X

Generative artificial intelligence (AI), such as ChatGPT, is rapidly becoming popular and is expected to be utilized in pharmacy practice; however, the current utilization status and usefulness of generative AI are not well understood. Therefore, we aimed to review its current utilization status and assess its potential for use in pharmacy practice.The literature review revealed that most studies evaluated the accuracy and completeness of responses from generative AI. ChatGPT-3.5 was reported to be less valuable owing to many errors but could be used in text summarization. ChatGPT-4 was reported to be superior to ChatGPT-3.5; however, its performance was still considered insufficient. The comparisons among the generative AIs were not sufficiently investigated. In conclusion, generative AI can potentially help clinical pharmacists in the future; however, its features and performance should be carefully monitored and evaluated using the latest version of generative AI when applied to pharmacy practice.

Kinetics of the inhibition of CYP3A4 and CYP2C19 activity by jabara juice and identification of the responsible inhibitory components

Koinuma K., Noto K., Morita T., Uekusa Y., Kikuchi H., Shimoji M., Seki H., Yamazaki H., Guengerich F.P., Nakamura K., Yamamoto K., Imaoka A., Akiyoshi T., Ohtani H.

Journal of Pharmaceutical Sciences 114 ( 2 ) 849 - 856 2025.02

ISSN 00223549

Some citrus fruits are known to cause clinically significant drug interactions by inhibiting intestinal cytochrome P450 (CYP) enzymes. This in vitro study aimed to investigate the kinetics of the inhibition of CYP3A4 and CYP2C19 by the juice of jabara, a Japanese citrus fruit that does not contain furanocoumarins such as 6′,7′-dihydroxybergamottin, and to identify the inhibitory compound(s). CYP3A4 and CYP2C19 activity levels were determined in vitro using recombinant CYP preparations and their respective substrates. The ethyl acetate extract (EAE) of jabara juice was separated to isolate and identify the compound(s) that inhibited CYP3A4. Then, the time-dependent kinetics of the inhibition of CYP3A4 and CYP2C19 by the EAE and its inhibitory compound(s) were analyzed. The EAE of jabara juice was found to inhibit CYP3A4 in a time-dependent manner. Two flavonoids, 3,3′,4′,5,6,7,8-heptamethoxyflavone (HpMF) and 3,3′,4′,5,6,7-hexamethoxyflavone (HxMF), were identified as the responsible compounds. HpMF and HxMF inhibited CYP3A4 activity in a concentration- and time-dependent manner, with inhibition constants (K<inf>I</inf>) of 10.0 and 7.90 µM and maximal inactivation rate constants (k<inf>inact,max</inf>) of 0.00856 and 0.0134 min−1, respectively. The EAE did not inhibit CYP2C19, even when preincubation was employed. These findings imply that jabara juice may cause food-drug interactions via time-dependent inhibition of intestinal CYP3A4.

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Medication counseling for OTC drugs using customized ChatGPT-4: Comparison with ChatGPT-3.5 and ChatGPT-4o

Kiyomiya K., Aomori T., Ohtani H.

Digital Health 11 20552076251323810 2025.01

ISSN 2055-2076

Background: In Japan, consumers can purchase most over-the-counter (OTC) drugs without pharmacist guidance. Recently, generative artificial intelligence (AI) has become increasingly popular. Therefore, medical professionals need to consider the use of generative AI by consumers for medication counseling. We have previously reported responses in Japanese from ChatGPT-3.5 to 264 questions regarding whether each of 22 OTC drugs can be taken under 12 typical patient conditions. The proportion of responses that satisfied the criteria of 1) accuracy, 2) relevance, and 3) reliability with respect to package insert instructions was 20.8%. In November 2023, GPTs were launched, enabling us to construct a customized ChatGPT, using natural language. In the present study, we compared performance in providing medication guidance among a newly customized GPT, the latest non-customized version ChatGPT-4o, and the previous version, ChatGPT-3.5. The aim was to determine whether the customization and version update of ChatGPT improved performance and to evaluate its potential usefulness. Methods: We configured customized ChatGPT-4 by executing five instructions in Japanese and uploaded the text of package inserts for 22 OTC drugs as knowledge. We asked the same 264 questions as in our previous study. Results: With the customized ChatGPT-4, the percentages of responses that satisfied the criteria of accuracy, relevance, and reliability were 93.2%, 100%, and 60.2%, respectively. Additionally, 56.1% of responses satisfied all three criteria, 2.7-fold higher compared with ChatGPT-3.5 and 1.3-fold higher compared with ChatGPT-4o. Conclusion: The performance of our customized GPT far exceeded that of ChatGPT-3.5. In particular, the proportion of appropriate responses to the questions using brand names was significantly improved. ChatGPT can be customized by providing drug package insert information and using appropriate prompt engineering, potentially offering helpful tools in clinical pharmacy.

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Performance Improvement of a Natural Language Processing Tool for Extracting Patient Narratives Related to Medical States From Japanese Pharmaceutical Care Records by Increasing the Amount of Training Data: Natural Language Processing Analysis and Validation Study

Ohno Y., Aomori T., Nishiyama T., Kato R., Fujiki R., Ishikawa H., Kiyomiya K., Isawa M., Mochizuki M., Aramaki E., Ohtani H.

Jmir Medical Informatics 13 e68863 2025

Background: Patients’ oral expressions serve as valuable sources of clinical information to improve pharmacotherapy. Natural language processing (NLP) is a useful approach for analyzing unstructured text data, such as patient narratives. However, few studies have focused on using NLP for narratives in the Japanese language. Objective: We aimed to develop a high-performance NLP system for extracting clinical information from patient narratives by examining the performance progression with a gradual increase in the amount of training data. Methods: We used subjective texts from the pharmaceutical care records of Keio University Hospital from April 1, 2018, to March 31, 2019, comprising 12,004 records from 6559 cases. After preprocessing, we annotated diseases and symptoms within the texts. We then trained and evaluated a deep learning model (bidirectional encoder representations from transformers combined with a conditional random field [BERT-CRF]) through 10-fold cross-validation. The annotated data were divided into 10 subsets, and the amount of training data was progressively increased over 10 steps. We also analyzed the causes of errors. Finally, we applied the developed system to the analysis of case report texts to evaluate its usability for texts from other sources. Results: The F<inf>1</inf>-score of the system improved from 0.67 to 0.82 as the amount of training data increased from 1200 to 12,004 records. The F<inf>1</inf>-score reached 0.78 with 3600 records and was largely similar thereafter. As performance improved, errors from incorrect extractions decreased significantly, which resulted in an increase in precision. For case reports, the F<inf>1</inf>-score also increased from 0.34 to 0.41 as the training dataset expanded from 1200 to 12,004 records. Performance was lower for extracting symptoms from case report texts compared with pharmaceutical care records, suggesting that this system is more specialized for analyzing subjective data from pharmaceutical care records. Conclusions: We successfully developed a high-performance system specialized in analyzing subjective data from pharmaceutical care records by training a large dataset, with near-complete saturation of system performance with about 3600 training records. This system will be useful for monitoring symptoms, offering benefits for both clinical practice and research.

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The Effects of N-Glycosylation on the Expression and Transport Activity of OATP1A2 and OATP2B1

Kataoka H., Akiyoshi T., Uchida Y., Imaoka A., Terasaki T., Ohtani H.

Journal of Pharmaceutical Sciences (Journal of Pharmaceutical Sciences) 113 ( 5 ) 1376 - 1384 2024.05

ISSN 00223549

Organic anion transporting polypeptide (OATP)1A2 and OATP2B1 have potential N-glycosylation sites, but their influence remains unclear. This study aimed to identify the N-glycosylation sites of OATP1A2/2B1 and investigate their impact on the expression and function of OATP1A2/2B1. Human embryonic kidney cells expressing OATP1A2 or OATP2B1 (HEK293-OATP1A2/2B1) were exposed to tunicamycin, an N-glycosylation inhibitor, and a plasma membrane fraction (PMF) Western blot assay and an estrone 3-sulfate (E3S) uptake study were conducted. HEK293-OATP1A2/OATP2B1 cell lines with mutation(s) at potential N-glycosylation sites were established, and the Western blotting and uptake study were repeated. Tunicamycin reduced the PMF levels and E3S uptake of OATP1A2/OATP2B1. The Asn124Gln, Asn135Gln, and Asn492Gln mutations in OATP1A2 and Asn176Gln and Asn538Gln mutations in OATP2B1 reduced the molecular weights of the OATP molecules and their PMF levels. The PMF levels of OATP1A2 Asn124/135Gln, OATP1A2 Asn124/135/492Gln, and OATP2B1 Asn176/538Gln were further reduced. The maximum transport velocities of OATP1A2 Asn124Gln, OATP1A2 Asn135Gln, and OATP2B1 Asn176/538Gln were markedly reduced to 10 %, 4 %, and 10 % of the wild-type level, respectively. In conclusion, the N-glycans at Asn124 and Asn135 of OATP1A2 and those at Asn176 and Asn538 of OATP2B1 are essential for the plasma membrane expression of these molecules and also affect their transport function.

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Comprehensive analysis of responses from ChatGPT to consumer inquiries regarding over-the-counter medications.

Kiyomiya K, Aomori T, Ohtani H

Die Pharmazie 79 ( 1 ) 24 - 28 2024.02

ISSN 0031-7144

Background: The use of generative artificial intelligence (AI) applications such as ChatGPT is becoming increasingly popular. In Japan, consumers can purchase most over-the-counter (OTC) drugs without having to consult a pharmacist, so they may ask generative AI applications which OTC drugs they should purchase. This study aimed to systematically evaluate responses from ChatGPT to consumer inquiries about various OTC drugs. Methods: We selected 22 popular OTC drugs and 12 typical consumer characteristics, including physical and disease conditions and concomitant medications. We input a total of 264 questions (i.e., all combinations of drugs and characteristics) to ChatGPT in Japanese, asking whether it is safe for consumers with each characteristic to take these OTC drugs. We used the generic name for 10 of the 22 drugs and the brand name for the remaining 12. Responses were evaluated based on the following three criteria: 1) coherence between the question and response, 2) scientific correctness, and 3) appropriateness of the instructed actions. When we received a response that satisfied all three criteria, we input the exact same question on a different day to assess reproducibility. Results: The proportions of ChatGPT's answers that satisfied criteria 1, 2, and 3 were 79.5%, 54.5%, and 49.6%, respectively. However, the proportion of responses that satisfied all three criteria was only 20.8% (55/264); 61.8% (34/55) of these responses were reproduced when the same question was input again on a different day. Compared with questions using generic names, those using brand names resulted in lower coherence and scientific correctness. Among the 12 characteristics, the appropriateness of the instructed actions tended to be lower in responses to questions about driving and concomitant medications. Conclusions: Our study revealed that ChatGPT was less accurate in its responses and less consistent in its instructed actions compared with the package inserts. Our findings suggest that Japanese consumers should not consult ChatGPT regarding OTC medications, especially when using brand names.

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Analysis of diseases and symptoms in medical documents by natural language processing

OHNO Yukiko, AOMORI Tohru, KIYOMIYA Keisuke, ISHIKAWA Haruki, NISHIYAMA Tomohiro, ISAWA Minae, MOCHIZUKI Mayumi, ARAMAKI Eiji, OHTANI Hisakazu

Proceedings of the Annual Conference of JSAI (The Japanese Society for Artificial Intelligence) JSAI2024 ( 0 ) 2S6OS7a03 - 2S6OS7a03 2024

New adverse events not detected in pre-marketing clinical trials sometimes emerge after medicines have entered the market. Therefore, systems that can extract the terminology of diseases and symptoms from unstructured data such as medical records are needed to enable automatic monitoring of adverse events. In this study, we analyzed nursing records of patients treated with vancomycin hydrochloride using a disease extraction system and a terminology list of allergic skin symptoms to identify cases with these symptoms and their occurrence frequency in a period with many occurrences and other period. The accuracy of the proposed method in detecting cases was assessed using the F-measure, which was found to be 0.71-0.74, and changes in the occurrence frequency between two periods were almost equal for the proposed method and visual confirmation by the researcher. These results suggest that the proposed method can be used for monitoring allergic skin symptoms due to vancomycin hydrochloride.

Determination of single-molecule transport activity of OATP2B1 by measuring the number of transporter molecules using electrophysiological approach

Yajima K., Akiyoshi T., Sakamoto K., Suzuki Y., Oka T., Imaoka A., Yamamura H., Kurokawa J., Ohtani H.

Journal of Pharmacological Sciences (Journal of Pharmacological Sciences) 153 ( 3 ) 153 - 160 2023.11

ISSN 13478613

Transporter-mediated clearance is determined by two factors, its single-molecule clearance, and expression level. However, no reliable method has been developed to evaluate them separately. This study aimed to develop a reliable method for evaluating the single-molecule activity of membrane transporters, such as organic anion transporting polypeptide (OATP) 2B1. HEK293 cells that co-expressed large conductance calcium-activated potassium (BK) channel and OATP2B1 were established and used for the following experiments. i) BK channel-mediated whole-cell conductance was measured using patch-clamp technique and divided by its unitary conductance to estimate the number of channels on plasma membrane (QI). ii) Using plasma membrane fraction, quantitative targeted absolute proteomics determined the stoichiometric ratio (ρ) of OATP2B1 to BK channel. iii) The uptake of estrone 3-sulfate was evaluated to calculate the Michaelis constant and uptake clearance (CL) per cell. Single-molecule clearance (CLint) was calculated by dividing CL by QI·ρ. QI and ρ values were estimated to be 916 and 2.16, respectively, yielding CLint of 5.23 fL/min/molecule. We successfully developed a novel method to reliably measure the single-molecule activity of a transporter, which could be used to evaluate the influences of factors such as genetic variations and post-translational modifications on the intrinsic activity of transporters.

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Irinotecan-induced gastrointestinal damage alters the expression of peptide transporter 1 and absorption of cephalexin in rats

Imaoka A., Hattori T., Akiyoshi T., Ohtani H.

Biopharmaceutics and Drug Disposition (Biopharmaceutics and Drug Disposition) 44 ( 5 ) 372 - 379 2023.10

ISSN 01422782

Irinotecan causes severe gastrointestinal damage, which may affect the expression of intestinal transporters. However, neither the expression of peptide transporter 1 (Pept1) nor the pharmacokinetics of Pept1 substrate drugs has been investigated under irinotecan-induced gastrointestinal damage. Therefore, the present study quantitatively investigated the effects of irinotecan-induced gastrointestinal damage on the intestinal expression of Pept1 and absorption of cephalexin (CEX), a typical Pept1 substrate, in rats. Irinotecan was administered intravenously to rats for 4 days to induce gastrointestinal damage. The expression of Pept1 mRNA and the Pept1 protein in the upper, middle, and lower segments of the small intestine of irinotecan-treated rats was assessed by quantitative real-time polymerase chain reaction (PCR) and western blotting, respectively. The pharmacokinetic profile of CEX was examined after its oral or intravenous administration (10 mg/kg). In irinotecan-treated rats, ∼2-fold increases in Pept1 protein levels were observed in all three segments, whereas mRNA levels remained unchanged. The oral bioavailability of CEX significantly decreased to 76% of that in control rats. The decrease in passive diffusion caused by intestinal damage may have overcome the increase in Pept1-mediated uptake. In conclusion, irinotecan may decrease the intestinal absorption of Pept1 substrate drugs; however, it increased the expression of intestinal Pept1.

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Quantitative Evaluation of the Impact of Ward-based Clinical Pharmacy Practices on the Workload of Physicians and Nurses

Sasaki Shunichi, Tsuda Soichiro, Kiyomiya Keisuke, Nakada Hideo, Muramatsu Hiroshi, Aomori Tohru, Ohtani Hisakazu

Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences) (Japanese Society of Pharmaceutical Health Care and Sciences) 49 ( 10 ) 357 - 364 2023.10

ISSN 1346-342X

The subjective and qualitative survey reported that ward-based clinical pharmacy practices were reported to be rated highly by physicians and nurses. However, no reports have quantitatively evaluated the reduction of their workload from the viewpoint of task-shifting to pharmacists from other medical professionals. In this study, we conducted a questionnaire survey of physicians and nurses working in wards receiving the pharmacy practices service in Keio University Hospital. Survey items include the reduction in the workload of physicians and nurses and subjective ratings regarding the performance of pharmacy practices. The ward-based pharmacy practices (5.9 hours/day, average for a ward) were estimated to be equivalent to the workloads of 3.1 and 2.6 hours/day for a physician and nurse, respectively, adding up to 36.1 hours of their workload per ward. More than 80％ of the responders positively rated the performance of pharmacy practices, except for sterile admixture. This is the first study to evaluate the quantitative contribution of ward-based pharmacy practices on task-shifting from physicians and nurses.

Comparison of Adverse Events between Diphenhydramine and Levocetirizine Pretreatment in Multiple Myeloma Patients Treated with Subcutaneous Daratumumab

Suehiro Naoya, Nagashima Ayano, Nishikawa Haru, Suzukawa Mayu, Sakurai Hiroomi, Muramatsu Hiroshi, Aomori Toru, Ohtani Hisakazu

Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences) (Japanese Society of Pharmaceutical Health Care and Sciences) 49 ( 8 ) 303 - 309 2023.08

ISSN 1346-342X

Subcutaneous daratumumab DARA-SC is superior to intravenous daratumumab with a significantly shorter treatment time for multiple myeloma. To prevent infusion reaction (IR) during DARA-SC, oral diphenhydramine, a first-generation antihistamine, has been used in the phase Ⅲ clinical trial and following clinical settings. We recently substituted diphenhydramine with levocetirizine, a second-generation antihistamine, to diminish antihistamine-induced sedation in our regimens for daratumumab.In this study, we aimed to retrospectively compare the prevention of IR and rate adverse events between diphenhydramine and levocetirizine. We retrospectively analyzed the clinical records of patients in whom DARA-SC treatment was introduced for the first time from August 1st, 2021 to July 31, 2022, at Keio University Hospital.For the first period, 7 and 24 patients were treated with diphenhydramine and levocetirizine, respectively. Neither patient experienced IR. Two out of 7 patients experienced drowsiness by diphenhydramine while only one of 24 patients experienced it by levocetirizine (P = 0.125). Five and one patients initially treated with diphenhydramine were switched to levocetirizine upon the second and third periods of DARA-SC treatment, respectively. After the switching, their drowsiness was reduced.In conclusion, levocetirizine was considered more beneficial than diphenhydramine to prevent IR with a lower rate of drowsiness.

The influence of temperature on the metabolic activity of CYP2C9, CYP2C19, and CYP3A4 genetic variants in vitro

Kojima M., Machida K., Cho S., Watanabe D., Seki H., Shimoji M., Imaoka A., Yamazaki H., Guengerich F.P., Nakamura K., Yamamoto K., Akiyoshi T., Ohtani H.

Xenobiotica (Xenobiotica) 53 ( 5 ) 357 - 365 2023

ISSN 00498254

1. Temperature is considered to affect the activity of drug-metabolizing enzymes; however, no previous studies have compared temperature dependency among cytochrome P450 genetic variants. This study aimed to analyse warfarin 7-hydroxylation by CYP2C9 variants; omeprazole 5-hydroxylation by CYP2C19 variants; and midazolam 1-hydroxylation by CYP3A4 variants at 34 °C, 37 °C, and 40 °C. 2. Compared with that seen at 37 °C, the intrinsic clearance rates (V max/K m) of CYP2C9.1 and.2 were decreased (76 ∼ 82%), while that of CYP2C9.3 was unchanged at 34 °C. At 40 °C, CYP2C9.1,.2, and.3 exhibited increased (121%), unchanged and decreased (87%) intrinsic clearance rates, respectively. At 34 °C, the clearance rates of CYP2C19.1A and.10 were decreased (71 ∼ 86%), that of CYP2C19.1B was unchanged, and those of CYP2C19.8 and.23 were increased (130 ∼ 134%). At 40 °C, the clearance rates of CYP2C19.1A,.1B,.10, and.23 remained unaffected, while that of CYP2C19.8 was decreased (74%). At 34 °C, the clearance rates of CYP3A4.1 and.16 were decreased (79 ∼ 84%), those of CYP3A4.2 and.7 were unchanged, and that of CYP3A4.18 was slightly increased (112%). At 40 °C, the clearance rate of CYP3A4.1 remained unaffected, while those of CYP3A4.2,.7,.16, and.18 were decreased (58 ∼ 82%). 3. These findings may be clinically useful for dose optimisation in patients with hypothermia or hyperthermia.

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The Effects of Jabara Juice on the Intestinal Permeation of Fexofenadine

Han Hongye, Akiyoshi Takeshi, Morita Tokio, Tsuchitani Toshiaki, Nabeta Momoko, Yajima Kodai, Imaoka Ayuko, Ohtani Hisakazu

Biological and Pharmaceutical Bulletin (The Pharmaceutical Society of Japan) 46 ( 12 ) 1745 - 1752 2023

ISSN 09186158

Jabara juice and its component narirutin inhibit the activity of organic anion-transporting polypeptides (OATPs) 1A2 and OATP2B1, which are considered to play significant roles in the intestinal absorption of fexofenadine. In this study, we investigated the effects of jabara juice on the intestinal absorption of fexofenadine in mice and the inhibitory effects of jabara juice and narirutin on the permeation of fexofenadine using Caco-2 cell monolayers and LLC-GA5-COL300 cell monolayers. In the in vivo study, the area under the plasma concentration–time curve (AUC) of fexofenadine in mice was increased 1.8-fold by jabara juice. In the permeation study, 5% jabara juice significantly decreased the efflux ratio (ER) of fexofenadine for Caco-2 monolayers. Furthermore, the ERs of fexofenadine and digoxin, which is a typical substrate of P-glycoprotein (P-gp), for LLC-GA5-COL300 cell monolayers were decreased in a concentration-dependent manner by jabara juice extract, suggesting that jabara juice may increase the intestinal absorption of fexofenadine by inhibiting P-gp, rather than by narirutin inhibiting OATPs. The present study showed that jabara juice increases the intestinal absorption of fexofenadine both in vivo and in vitro. The intestinal absorption of fexofenadine may be altered by the co-administration of jabara juice in the clinical setting.

Comparison of the transport kinetics of fexofenadine and its pH dependency among OATP1A2 genetic variants

Han H., Akiyoshi T., Morita T., Kataoka H., Katayama K., Yajima K., Imaoka A., Ohtani H.

Drug Metabolism and Pharmacokinetics (Drug Metabolism and Pharmacokinetics) 47 100470 2022.12

Research paper (scientific journal), Last author, Corresponding author, Accepted, ISSN 13474367

Little is known about the influence of non-synonymous genetic variations in the organic anion-transporting polypeptide (OATP) 1A2 on the transport kinetics of its substrate fexofenadine. Moreover, the pH-dependency of fexofenadine uptake also remains unclear. This study aimed to evaluate the effects of genetic variants (Ile13Thr, Asn128Tyr, Glu172Asp, Ala187Thr, and Thr668Ser) on the OATP1A2-mediated uptake of fexofenadine at pH 6.3 and 7.4 and compare the pH dependency of OATP1A2-mediated uptake of fexofenadine and estrone 3-sulfate. The uptake clearances of 0.3 μM and 300 μM fexofenadine were compared with those of 0.3 μM and 300 μM estrone 3-sulfate at pH 6.3 and 7.4. Among the six variants examined, the Thr668Ser variant showed the highest fexofenadine uptake clearance (Vmax/Km); i.e., 4.53- and 6.28-fold higher uptake clearance than the wild type at pH 6.3 and 7.4, respectively. All variants exhibited significantly higher fexofenadine uptake at pH 6.3 than at pH 7.4. Compared with estrone 3-sulfate uptake, the uptake of 0.3 μM fexofenadine was less sensitive to pH. Our findings suggest that genetic variations in OATP1A2 may lead to altered intestinal absorption of fexofenadine, such as increased absorption in subjects bearing the Thr668Ser variant, which showed higher uptake activity.

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医薬品情報の科学的な収集、評価、活用

大谷壽一

The Annual Meeting of Japanese Society of Pharmaceutical Health Care and Sciences (Japanese Society of Pharmaceutical Health Care and Sciences) 32 ( 0 ) 99 - 99 2022.09

Research paper (other academic)

Inhibitory Effects of Cranberry Juice and Its Components on Intestinal OATP1A2 and OATP2B1: Identification of Avicularin as a Novel Inhibitor

Morita T., Akiyoshi T., Tsuchitani T., Kataoka H., Araki N., Yajima K., Katayama K., Imaoka A., Ohtani H.

Journal of Agricultural and Food Chemistry (Journal of Agricultural and Food Chemistry) 70 ( 10 ) 3310 - 3320 2022.03

Research paper (scientific journal), Joint Work, Accepted, ISSN 00218561

Organic anion-transporting polypeptide (OATP) 1A2 and OATP2B1 mediate the intestinal absorption of drugs. This study aimed to identify fruit juices or fruit juice components that inhibit OATPs and assess the risk of associated food-drug interactions. Inhibitory potency was assessed by examining the uptake of [3H]estrone 3-sulfate and [3H]fexofenadine into HEK293 cells expressing OATP1A2 or OATP2B1. In vivo experiments were conducted using mice to evaluate the effects of cranberry juice on the pharmacokinetics of orally administered fexofenadine. Of eight examined fruit juices, cranberry juice inhibited the functions of both OATPs most potently. Avicularin, a component of cranberry juice, was identified as a novel OATP inhibitor. It exhibited IC50values of 9.0 and 37 μM for the inhibition of estrone 3-sulfate uptake mediated by OATP1A2 and OATP2B1, respectively. A pharmacokinetic experiment revealed that fexofenadine exposure was significantly reduced (by 50%) by cranberry juice. Cranberry juice may cause drug interactions with OATP substrates.

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Analysis of inhibition kinetics of three beverage ingredients, bergamottin, dihydroxybergamottin and resveratrol, on CYP2C9 activity

Akiyoshi T., Uchiyama M., Inada R., Imaoka A., Ohtani H.

Drug Metabolism and Pharmacokinetics (Drug Metabolism and Pharmacokinetics) 42 100429 2022.02

Research paper (scientific journal), Joint Work, Last author, Corresponding author, Accepted, ISSN 13474367

Some grapefruit juice (GFJ) ingredients and resveratrol, a fruit-derived phytoalexin, are known to inhibit cytochrome P450 (CYP) 2C9. However, their inhibition modes and detailed inhibition kinetics remain undetermined. This study aimed to investigate the inhibitory effects of two GFJ ingredients, bergamottin (BG) and dihydroxybergamottin (DHB), and resveratrol on CYP2C9 activity in vitro. DHB inhibited CYP2C9 activity, as assessed by warfarin 7-hydroxylation, in a preincubation time-dependent manner (i.e., mechanism-based inhibition; MBI), in the same manner as CYP2C19 and CYP3A4. The maximal inactivation rate (kinact,max) was 0.0638 min−1 and 0.12- and 0.26-fold of that for CYP2C19 and CYP3A4, respectively. BG showed both MBI and time-independent competitive inhibition. Resveratrol showed non-competitive inhibition with an inhibition constant (Ki) of 3.64 μM. Unlike the inhibition of CYP2C19 and CYP3A4, resveratrol did not induce MBI. These findings are important for estimating the risk of drug interactions between CYP2C9 substrates and some beverages. (146 words)

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Evaluation of hepatic CYP3A enzyme activity using endogenous markers in lung cancer patients treated with cisplatin, dexamethasone, and aprepitant.

Hibino H, Sakiyama N, Makino Y, Makihara-Ando R, Horinouchi H, Fujiwara Y, Kanda S, Goto Y, Yoshida T, Okuma Y, Shinno Y, Murakami S, Hashimoto H, Akiyoshi T, Imaoka A, Ohe Y, Yamaguchi M, Ohtani H

European Journal of Clinical Pharmacology (Eur J Clin Pharmacol) 78 ( 4 ) 613 - 621 2022

Research paper (scientific journal), Joint Work, Accepted, ISSN 00316970

Purpose: Aprepitant is used with dexamethasone and 5-HT3 receptor antagonists as an antiemetic treatment for chemotherapy, including cisplatin. Aprepitant is a substrate of cytochrome P450 (CYP) 3A4 and is known to cause its inhibition and induction. In addition, dexamethasone is a CYP3A4 substrate that induces CYP3A4 and CYP3A5 expression. In this study, we aimed to quantitatively evaluate the profile of CYP3A activity using its endogenous markers in non-small cell lung cancer patients receiving a standard cisplatin regimen with antiemetics, including aprepitant. Methods: Urinary 11β-hydroxytestosterone (11β-OHT)/testosterone concentration ratio and plasma 4β-hydroxycholesterol (4β-OHC) concentrations were measured before and after cisplatin treatment (days 1, 4, and 8). CYP3A5 was genotyped, and plasma aprepitant concentrations were measured on day 4 to examine its influence on CYP3A endogenous markers. Results: The urinary 11β-OHT/testosterone concentration ratio in the 35 patients included in this study increased by 2.65-fold and 1.21-fold on days 4 and 8 compared with day 1, respectively. Their plasma 4β-OHC concentration increased by 1.46-fold and 1.66-fold, respectively. The mean plasma aprepitant concentration on day 4 was 1,451 ng/mL, which is far lower than its inhibitory constant. The allele frequencies of CYP3A5*1 and CYP3A5*3 were 0.229 and 0.771, respectively. In patients with the CYP3A5*1 allele, the plasma 4β-OHC concentration was significantly lower at baseline but more potently increased with chemotherapy. Conclusion: CYP3A activity was significantly induced from day 4 to day 8 in patients receiving cisplatin and three antiemetic drugs.

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Mechanistic bottom-up estimation of passive drug absorption from the gastrointestinal tract– Comparison among primary cultured human intestinal cells, Caco-2 cells, artificial membranes, and animal scale-up

Tsuchitani T, Akiyoshi T, Imaoka A, Ohtani H

Int J Clin Pharmacol Ther (International Journal of Clinical Pharmacology and Therapeutics) 60 ( 5 ) 217 - 224 2022

Research paper (scientific journal), Joint Work, Last author, Corresponding author, Accepted, ISSN 0946-1965

Objective: The fraction of drug absorbed (Fa) from the intestine is an important parameter to characterize the pharmacokinetics of a drug. We aimed to search for an experimental system that provides the best parameters for estimating the effective permeability (Peff) used for the bottom-up prediction of Fa. Materials and methods: The absorption kinetics of 12 passively absorbed drugs were simulated by a compartment absorption transit (CAT) model using absorption parameters from four different experimental systems: human intestinal epithelial cell (HIEC) monolayer, Caco-2 monolayer, parallel artificial membrane permeability assay (PAMPA), and in situ rat intestinal perfusion. All absorption parameters were obtained from the literature. The in vitro apparent permeability coefficient (Papp) and rat in situ Peff were converted to human Peff using a bottom-up approach for each region, based on the morphological features of the human intestine. The simulated Fa values were compared to the respective observed values. Furthermore, plasma concentration profiles of the drugs were simulated by convolution using the time-course of the absorption rate simulated using the Peff values calculated from the HIEC Papp. Results: The Fa values were best predicted by using the Peff values calculated from HEIC, within a 1.3-fold range of observed Fa in 11 out of 12 drugs. The simulated Cmax values of pharmacokinetic simulation using HIEC Papp fell within a 1.5-fold range of observed values for all the drugs examined. Conclusion: The HIEC monolayer was identified as the most suitable permeation parameter for estimating Fa and Cmax using a morphological feature-based bottom-up approach.

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Comparison of the inhibitory properties of the fruit component naringenin and its glycosides against OATP1A2 genetic variants.

Araki N, Morita T, Akiyoshi T, Kataoka H, Yajima K, Katayama K, Imaoka A and Ohtani H.

Drug Metabol Pharmacokinet 46 2022

Research paper (scientific journal), Joint Work, Last author, Corresponding author, Accepted

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Time-dependent inhibition of CYP3A4-mediated midazolam metabolism by macrolide antibiotics in CYP3A4 genetic variants: Comparison with testosterone metabolism

Akiyoshi Takeshi, Naitou Rina, Imaoka Ayuko, Miyazaki Mitsue, Guengerich F. Peter, Nakamura Katsunori, Yamamoto Koujiro, Ohtani Hisakazu

INTERNATIONAL JOURNAL OF CLINICAL PHARMACOLOGY AND THERAPEUTICS (International Journal of Clinical Pharmacology and Therapeutics) 59 ( 12 ) 745 - 752 2021.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 0946-1965

Objectives: The present study aimed to evaluate the effects of CYP3A4 genetic variation on the kinetics of mechanismbased inhibition (MBI) of both inhibitors using midazolam as a substrate for comparison with our previous study, as midazolam and testosterone have different binding sites. Background: The genetic variation of cytochrome P450 (CYP) 3A4 affects MBI, expressed as the maximum inactivation rate constant (kinact,max) and the inhibitor concentration required to achieve half-maximal inactivation (KI). We previously showed, using testosterone as a substrate, that the MBI kinetics of erythromycin and clarithromycin differ among CYP3A4 variants. Materials and methods: Midazolam 1'-hydroxylation inactivation profiles of erythromycin and clarithromycin were assessed using recombinant CYP3A4.1, .2, .7, .16, and .18 expressed in Escherichia coli. MBI parameters were calculated from changes in the inactivation rate constant (Δkobs) by the inhibitors. Results: Both inhibitors increased Δkobs value in a concentration- and preincubation time-dependent manner, and MBI kinetics differed among variants. Trends of differences in MBI parameters among variants were similar to those assessed using testosterone as a substrate; KI decreased for CYP3A4.7, and kinact,max decreased for CYP3A4.2, .7, and .16. Conclusion: The genetic variation of recombinant CYP3A4 affects the MBI profile of CYP3A4 by erythromycin and clarithromycin, while the influence of genetic variation was similarly observed regardless of substrates. Our findings are of clinical relevance because the residual enzyme activity of CYP3A4 in the presence of inhibitor was estimated to vary among genetic variants.

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Dual kinetics of OATP2B1: Inhibitory potency and pH-dependence of OATP2B1 inhibitors

Sato R., Akiyoshi T., Morita T., Katayama K., Yajima K., Kataoka H., Imaoka A., Ohtani H.

Drug Metabolism and Pharmacokinetics (Drug Metabolism and Pharmacokinetics) 41 100416 2021.12

Research paper (scientific journal), Accepted, ISSN 13474367

Organic anion transporting polypeptide (OATP) 2B1 is expressed in the intestine and liver, and OATP2B1-mediated transport of estrone 3-sulfate is pH-dependent and consists of: the high-affinity component (Hc) and low-affinity component (Lc). This study aimed to evaluate the influence of pH on the transport kinetics of each component, along with the inhibitory nature of ten OATP2B1 inhibitors. The Michaelis constants (Km) were 4-fold and 1.5-fold lower at pH 6.3 than at pH 7.4, for Hc and Lc respectively. The inhibitory potencies of diclofenac, indomethacin, and ibuprofen towards Hc were 1.5–4.3 fold lower at pH 6.3 than at pH 7.4. Contrastingly, inhibitory potencies towards Lc were 9.0–52 fold lower at pH 7.4. Similarly, the inhibitory effect of naproxen was stronger towards Hc at pH 6.3 and towards Lc at pH 7.4. On the other hand, celecoxib selectively inhibited Lc transport at pH 7.4. Rifampicin inhibited both components at pH 6.3 and 7.4 to a similar extent, while bromosulphophthalein, naringin, and gefitinib selectively inhibited Hc irrespective of pH. Fexofenadine inhibited neither component. In conclusion, the transport affinities of both Hc and Lc were enhanced under acidic conditions. The influence of pH on the inhibitory potency towards each component varied among the inhibitors.

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Digoxin absorption decreased independently of P-gp activity in rats with irinotecan-induced gastrointestinal damage

Tsuchitani Toshiaki, Akiyoshi Takeshi, Imaoka Ayuko, Ohtani Hisakazu

JOURNAL OF PHARMACEUTICAL HEALTH CARE AND SCIENCES (Journal of Pharmaceutical Health Care and Sciences) 7 ( 1 ) 24 2021.07

Research paper (scientific journal), Joint Work, Accepted, ISSN 2055-0294

Background: Irinotecan (CPT-11) is clinically known to cause severe diarrhea and gastrointestinal damage. Recently, we have reported that CPT-11-induced gastrointestinal damage is associated with the upregulation of intestinal P-glycoprotein (P-gp) expression and decreased absorption of its substrate, dabigatran etexilate (DABE), using a rat model. However, the P-gp activity or its contribution to the decreased absorption remains unclear. The aim of this study was to quantitatively evaluate how P-gp activity changes in rats with CPT-11-induced gastrointestinal damage, as assessed by the absorption of digoxin (DGX), a typical P-gp substrate. Methods: Male Sprague-Dawley rats were intravenously administered CPT-11 at a dose of 60 mg/kg/day for 4 days to induce gastrointestinal damage. Then, the rats were administered DGX orally (40 μg/kg), after some of them were orally administered clarithromycin (CAM; 10 mg/kg), a P-gp inhibitor. DGX (30 μg/kg) was administered intravenously to determine the bioavailability (BA). The rats’ DGX plasma concentration profiles were determined using LC-MS/MS. Results: CPT-11 treatment decreased the maximum concentration (Cmax) and area under the plasma concentration-time curve (AUCpo) of DGX, which does not contradict to the DABE study. Although in the CPT-11-treated group the BA of DGX was significantly decreased to 40% of the control value, CAM did not affect the BA of DGX in the CPT-11-treated group. Conclusions: Increased P-gp expression in rats with CPT-11-induced gastrointestinal damage is not necessarily associated with increased P-gp activity or contribution to the drug absorption in vivo. The decreased DGX absorption observed in this study might be attributable to other factors, such as a reduction in the absorptive surface area of the gastrointestinal tract.

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Estimation of absolute oral bioavailability without performing an intravenous clinical study

Ohtani H., Iwata R., Imaoka A., Akiyoshi T.

Drug Metabolism and Pharmacokinetics (Drug Metabolism and Pharmacokinetics) 38 100392 2021.06

Research paper (scientific journal), Accepted, ISSN 13474367

The absolute oral bioavailability (BA) of drugs are yet to be determined, and intravenous pharmacokinetic studies are currently considered indispensable for determining the BA values of oral drugs. The aim of this study was to develop and validate a novel approach to estimating BA values without intravenous pharmacokinetic data. Based on the drug inclusion criteria, such as exhibiting a urinary recovery rate of (Ru) of ≥20% in a clinical study, 13 drugs were included in the present study, and pharmacokinetic data for them were collected from the literature. The fraction excreted unchanged into urine (fe) was calculated for healthy subjects by dividing the Ru value by the total recovery rate. The contribution of renal excretion to total clearance from the systemic circulation (Rren) was estimated by subjecting oral clearance and creatinine clearance to regression in subjects with normal and impaired renal function. BA was estimated as fe/Rren and compared with the observed BA (BAobs). The predicted BA values for 9 drugs fell within ±20% of their BAobs. The examined approach makes it possible to estimate BA values for drugs with mean renal excretion values in healthy subjects and oral clearance in subjects with various renal function, without intravenous pharmacokinetic data.

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Comparison of the inhibitory effects of azole antifungals on cytochrome P450 3A4 genetic variants

Yamaguchi Y., Akiyoshi T., Kawamura G., Imaoka A., Miyazaki M., Guengerich F.P., Nakamura K., Yamamoto K., Ohtani H.

Drug Metabolism and Pharmacokinetics (Drug Metabolism and Pharmacokinetics) 38 100384 2021.06

Research paper (scientific journal), Accepted, ISSN 13474367

Cytochrome P450 (CYP) 3A4 is one of the major drug-metabolizing enzymes. Genetic variants of CYP3A4 with altered activity are one of the factors responsible for interindividual differences in drug metabolism. Azole antifungals inhibit CYP3A4 to cause clinically significant drug-drug interactions. In the present quantitative study, we investigated the inhibitory effects of three azole antifungals (ketoconazole, voriconazole, and fluconazole) on testosterone metabolism by recombinant CYP3A4 genetic variants (CYP3A4.1 (WT), CYP3A4.2, CYP3A4.7, CYP3A4.16, and CYP3A4.18) and compared them with those previously reported for itraconazole. The inhibition constants (Ki) of ketoconazole, voriconazole, and fluconazole for rCYP3A4.1 were 3.6 nM, 3.2 μM, and 16.1 μM, respectively. The Ki values of these azoles for rCYP3A4.16 were 13.9-, 13.6-, and 6.2-fold higher than those for rCYP3A4.1, respectively, whereas the Ki value of itraconazole for rCYP3A4.16 was 0.54-fold of that for rCYP3A4.1. The other genetic variants had similar effects on the Ki values of the three azoles, whereas a very different pattern was seen for itraconazole. In conclusion, itraconazole has unique characteristics that are distinct from those shared by the other azole anti-fungal drugs ketoconazole, voriconazole, and fluconazole with regard to the influence of genetic variations on the inhibition of CYP3A4.

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Exacerbation of atrioventricular block associated with concomitant use of amlodipine and aprepitant in a lung cancer patient: A case report

Hibino H., Makino Y., Sakiyama N., Makihara-Ando R., Hashimoto H., Akiyoshi T., Imaoka A., Fujiwara Y., Ohe Y., Yamaguchi M., Ohtani H.

International Journal of Clinical Pharmacology and Therapeutics (International Journal of Clinical Pharmacology and Therapeutics) 59 ( 4 ) 328 - 332 2021.04

Research paper (scientific journal), Accepted, ISSN 09461965

Objective: To report a case of second-degree atrioventricular block associated with concomitant use of aprepitant and amlodipine. Case: A 73-year-old man with lung cancer was treated with aprepitant for prophylactic use for the prevention of nausea and vomiting, concomitantly with cisplatin, gemcitabine, and an investigational drug (anti-epidermal growth factor receptor monoclonal antibody). He was diagnosed with first-degree atrioventricular block and was taking amlodipine for hypertension. During the first cycle of chemotherapy, 5 days after the start of aprepitant, he experienced Wenckebach second-degree atrioventricular block (Mobitz type I), and amlodipine was discontinued. After day 6, the atrioventricular block was not shown. According to the Naranjo adverse drug reaction scale, a score of 7 was obtained (causality: probable). In addition, using the Drug Interaction Probability Scale, a score of 6 was obtained (causality: probable). Conclusion: The drug-drug interaction between aprepitant and amlodipine was considered to have deteriorated his atrioventricular block, conceivably due to the inhibition of cytochrome P450 (CYP) 3A-mediated metabolism of amlodipine by aprepitant.

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Relative contributions of metabolic enzymes to systemic elimination can be estimated from clinical DDI studies - validation using an in silico approach -

Koinuma K., Tsuchitani T., Imaoka A., Akiyoshi T., Ohtani H.

International Journal of Clinical Pharmacology and Therapeutics (International Journal of Clinical Pharmacology and Therapeutics) 59 ( 3 ) 231 - 238 2021

Research paper (scientific journal), Joint Work, Accepted, ISSN 09461965

Objective: The contribution ratios (CR) of metabolic enzymes to the systemic clearance of a drug can be estimated from in vitro studies. Another feasible approach is to calculate them based on the increase in the area under the time-concentration curve (AUC) caused by the co-administration of a potent and selective inhibitor in a clinical drug-drug interaction (DDI) study. However, some factors, such as the inhibitory potency of the inhibitor and the inhibition of first-pass metabolism, might affect the estimation of CR based on clinical DDI studies. We aimed to validate the accuracy of the DDI-based estimation of CR using an in silico approach. Materials and methods: An in silico DDI study was conducted using a population-based physiological pharmacokinetic simulator to estimate the CR of cytochrome P450 (CYP)3A4 for zolpidem, sildenafil, omeprazole, triazolam, and repaglinide. The ratio of the AUC value seen in the presence of an inhibitor (ketoconazole or itraconazole) to that observed in the absence of the inhibitor (AUC ratio) was also calculated. The CR for CYP3A4 obtained using the simulator (CRdef) were compared with those calculated from the AUC ratio (CRest). Results: When ketoconazole was used, good correlations between the CRest and CRdef were obtained for all examined substrates (inconsistencies were seen in < 10% of subjects). CR estimates derived from the AUC ratio were found to be accurate. Some underestimation was observed, possibly due to incomplete inhibition, and some overestimation caused by extensive first-pass metabolism was noted. Conclusion: This study verified that CR obtained from AUC ratios in DDI studies are quite reliable.

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Novel method to estimate the appropriate dosing interval for activated charcoal to avoid interaction with other drugs

Ohtani H., Nakamura K., Imaoka A., Akiyoshi T.

European Journal of Clinical Pharmacology (European Journal of Clinical Pharmacology) 76 ( 11 ) 1529 - 1536 2020.11

Research paper (scientific journal), Accepted, ISSN 00316970

© 2020, Springer-Verlag GmbH Germany, part of Springer Nature. Purpose: Activated charcoal is known to adsorb a variety of drugs concomitantly administered and reduce their intestinal absorption, and separating the dosing is considered a practical approach to avoid this drug interaction. The aim of the present study was to develop and validate a simple method to estimate the sufficient dosing interval to avoid drug interaction using the pharmacokinetic profile of the subject drugs administered alone and the amplitude of interaction upon simultaneous administration with activated charcoal. Methods: For each subject drug, the pharmacokinetic profile and the amplitude of interaction, as assessed by AUCR (the ratio of area under the plasma concentration-time curve (AUC) in the presence of activated charcoal to that in its absence), were collected from previous reports. The AUCR value was estimated based on the compartment model under the assumption that the subject drug in the first gastrointestinal compartment is immediately adsorbed to a certain extent upon the administration of activated charcoal. The estimated AUCR (AUCRe) for each drug with certain dosing interval was compared with the respective AUCR value reported previously (AUCRobs). Results: Among twenty concentration profiles for 14 subject drugs obtained from previous reports, 15 AUCRe values fell in the range of 80–120% of the respective AUCRobs values. Conclusion: The developed method enabled estimation of the amplitude of DDI by activated charcoal administered in a certain dosing interval, whereas overestimation of AUCRe was observed for drugs that undergo extensive enterohepatic circulation.

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Profile of the inhibitory effects of gefitinib in CYP2D6 variants in vitro

Semba Y., Akiyoshi T., Hibino H., Imaoka A., Ohtani H.

International Journal of Clinical Pharmacology and Therapeutics (International Journal of Clinical Pharmacology and Therapeutics) 58 ( 10 ) 539 - 542 2020.10

Research paper (scientific journal), Accepted, ISSN 09461965

© 2020 Dustri-Verlag Dr. K. Feistle. Objective: CYP2D6 is a highly polymorphic metabolic enzyme with more than 100 genetic variants, some of which are associated with significantly altered enzyme activity, such as CYP2D6.2 (Arg296Cys, Ser486Thr), CYP2D6.10 (Pro34Ser, Ser486Thr), and CYP2D6.39 (Ser486Thr). Gefitinib is a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR) and is used to treat non-small-cell lung cancer with EGFR mutations. Gefitinib is known to competitively inhibit CYP2D6 activity. The aim of this study was to quantitatively compare the inhibitory effects of gefitinib on CYP2D6 enzyme kinetics among CYP2D6 variants. Materials and methods: The enzymatic activity of several CYP2D6 genetic variants; i.e., CYP2D6.1 (wild type), CYP2D6.2, CYP2D6.10, and CYP2D6.39, was assessed by examining the O-demethylation of dextromethorphan. Results and conclusion: The intrinsic clearance of dextromethorphan (Vmax/Km) for CYP2D6.2, CYP2D6.10, and CYP2D6.39 were 0.565-, 0.0376-, and 0.470-fold of that for wild type, respectively. For all variants, the mixed inhibition model was better at explaining the nature of the inhibitory effects of gefitinib than the competitive inhibition model. However, the inhibitory potency of gefitinib varied among the CYP2D6 genetic variants. The Ki values for CYP2D6.2, CYP2D6.10, and CYP2D6.39 were 1.4-, 2.5- and 1.5-fold higher than that for wild type, respectively, implying that these variants are less susceptible to the inhibition by gefitinib. The genetic variations in CYP2D6 might be one of the factors responsible for inter-individual differences in the strength of CYP2D6-mediated drug interactions involving gefitinib.

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pH-dependent transport kinetics of the human organic anion-transporting polypeptide 1A2

T. Morita, T Akiyoshi, R. Sato, K. Katayama, K. Yajima, H. Kataoka, A. Imaoka, Y. Sugimoto, H. Ohtani

Drug Metabolism and Pharmacokinetics (Drug Metabolism and Pharmacokinetics) 35 ( 2 ) 220 - 227 2020

Research paper (scientific journal), Joint Work, Accepted, ISSN 13474367

© 2019 The Japanese Society for the Study of Xenobiotics Organic anion-transporting polypeptide (OATP) 1A2 is expressed on the apical sides of intestinal and renal epithelial cells and considered to be involved in the intestinal absorption and renal reabsorption of drugs. Although the transport activity of OATP1A2 is considered to be pH-dependent, the effects of pH on its kinetic parameters and on the potency of OATP1A2 inhibitors are yet to be elucidated. Some OATP are known to have multiple binding sites (MBS), but it remains unclear whether OATP1A2 has MBS. In the present study, we evaluated the influence of pH on the OATP1A2-mediated uptake of estrone 3-sulfate using OATP1A2-expressing HEK293 cells. The uptake of 0.3 μM estrone 3-sulfate by HEK293-OATP1A2 cells was pH-dependent. OATP1A2 exhibited bimodal saturation kinetics at pH 6.3 and 7.4. Compared with that seen at pH 6.3 (5.62 μM), the Km value of the high-affinity site was 8-fold higher at pH 7.4 (43.2 μM). In addition, the influence of pH on the potency of inhibitors varied among the examined inhibitors. These results suggest that the transport properties of OATP1A2 under lower pH conditions, such as those found in the microenvironments of the small intestinal mucosa and distal tubules, differ from those seen under neutral pH conditions.

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The citrus fruit-derived flavanone glycoside narirutin is a novel potent inhibitor of organic anion-transporting polypeptides

Morita T, Akiyoshi T, Sato R, Uekusa Y, Katayama K, Yajima K, Imaoka A, Sugimoto Y, Kiuchi F, Ohtani H

Journal of Agricultural and Food Chemistry (Journal of Agricultural and Food Chemistry) 68 ( 48 ) 14182 - 14191 2020

Research paper (scientific journal), Joint Work, Accepted, ISSN 00218561

© Organic anion-transporting polypeptides (OATPs) 1A2 and OATP2B1 are expressed in the small intestine and are involved in drug absorption. We identified narirutin, which is present in grapefruit juice, as a novel OATP inhibitor. The citrus fruit jabara also contains high levels of narirutin; therefore, we investigated the inhibitory potency of jabara juice against OATPs. The inhibitory effects of various related compounds on the transport activity of OATPs were evaluated using OATP-expressing HEK293 cells. The IC50 values of narirutin for OATP1A2- and OATP2B1-mediated transport were 22.6 and 18.2 μM, respectively. Other flavanone derivatives from grapefruit juice also inhibited OATP1A2/OATP2B1-mediated transport (order of inhibitory potency: naringenin > narirutin > naringin). Five percent jabara juice significantly inhibited OATP1A2- and OATP2B1-mediated transport by 67 ± 11 and 81 ± 5.5%, respectively (p < 0.05). Based on their inhibitory potency and levels in grapefruit juice, the inhibition of OATPs by grapefruit juice is attributable to both naringin and narirutin. Citrus × jabara, which contains narirutin, potently inhibits OATP-mediated transport.

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Pharmacy Customers' Awareness of the Illegality of Transferring Drugs to a Third Party

Ohtani Hisakazu, Fujii Honomi, Imaoka Ayuko, Mochizuki Mayumi, Yamaura Katsunori, Akiyoshi Takeshi

Iyakuhin Johogaku (Japanese Society of Drug Informatics) 22 ( 1 ) 30 - 34 2020

Research paper (scientific journal), Joint Work, Accepted, ISSN 1345-1464

Background: Although transferring drugs to a third party, even in a personal capacity, is illegal in Japan, many drug transactions are carried out via internet auction sites. Pharmacy consumers might not be aware of the illegality of transferring drugs to others due to various factors. To clarify pharmacy consumers' awareness of this issue and its covariates, we carried out a questionnaire survey.Methods: A self-completed questionnaire, consisting of yes/no and multiple-choice questions, was used. The adult patients who visited Keio University Pharmacy were asked to fill out the questionnaire.Results and Discussion: One hundred and fifty-one response sheets were effectively collected from 173 responders. The subjects'awareness of the illegality of transferring drugs was significantly affected by the formulation (oral vs. patches) and pharmacological category of the drug, as well as the source of the drug (prescribed vs. over the counter). Patient education about the illegality of personally transferring drugs, especially patches, might be required to avoid illegal drug transfers, including via the internet.

Irinotecan-induced gastrointestinal damage impairs the absorption of dabigatran etexilate

Hattori T., Imaoka A., Akiyoshi T., Ohtani H.

Biopharmaceutics and Drug Disposition (Biopharmaceutics and Drug Disposition) 40 ( 9 ) 315 - 324 2019.11

Research paper (scientific journal), Accepted, ISSN 01422782

© 2019 John Wiley & Sons, Ltd. Irinotecan causes serious gastrointestinal damage. Dabigatran etexilate (DABE), an oral anticoagulant and substrate of P-glycoprotein (P-gp), is poorly absorbed and exhibits low bioavailability in humans. The aim of this study was to evaluate the effects of irinotecan-induced gastrointestinal damage on the pharmacokinetics/pharmacodynamics (PK/PD) of DABE. Irinotecan was administered intravenously to rats for 4 days to induce gastrointestinal damage. To investigate the PK profile of dabigatran (DAB), an active moiety of DABE, DABE was administered orally on day 5, and then DAB was administered intravenously on day 6. To evaluate the PD profile of DAB, the activated partial thromboplastin time (APTT) was measured. The protein expression level of intestinal P-gp was evaluated. In the irinotecan-treated rats, the area under the concentration–time curve of DAB after the oral administration of DABE and the bioavailability of DABE were decreased significantly. The APTT ratio also decreased, suggesting that the impaired efficacy of DABE was attributable to a reduction in its bioavailability. The expression of intestinal P-gp was higher in the irinotecan-treated rats. Taking into consideration the histological damage caused to the intestinal epithelium, both the increased P-gp expression and the reduced passive diffusion were considered to be responsible for the reduction in the bioavailability of DABE.

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Current Status of Unapproved Drug Transactions via Internet Auction in Japan

Ohtani Hisakazu, Fujii Honomi, Imaoka Ayuko, Akiyoshi Takeshi

Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences) (Japanese Society of Pharmaceutical Health Care and Sciences) 45 ( 10 ) 591 - 595 2019.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 1346-342X

In Japan, purchasing drugs via Internet auction is prohibited by law. The aim of the present study was to clarify the current status of unapproved drug transactions via Internet auction in Japan. We created five sets of keywords corresponding to five therapeutic categories, ie, hair growth, gastrointestinal treatment, skin care, anti-aging therapy, and anti-cancer therapy. The searches were first performed on the website "Yahoo-oku" (Yahoo auction, Japan) using the above sets of keywords within five days, followed by secondary searches in the same manner after a forty-day interval. The searched items together with their explanations were evaluated independently by two researchers to determine whether they were illegal. The illegal items in the anti-cancer category were further monitored after submitting violation reports to the website. In two search phases within five days each, 571 and 581 illegal items were identified, respectively. After submission of the violation reports, only 1.1％ and 3.4％ of the items in the anti-cancer category were withdrawn by the site administrator and seller, respectively, and 38％ of the monitored items were sold. Taken together, unapproved drug transactions via the Internet are a serious problem. The government and site administrators may need to take effective measures to monitor and avoid such transactions, as well as providing notices and education to customers.

Effects of food type on the extent of drug-drug interactions between activated charcoal and phenobarbital in rats

Ogata Y., Imaoka A., Akiyoshi T., Ohtani H.

Drug Metabolism and Pharmacokinetics (Drug Metabolism and Pharmacokinetics) 34 ( 4 ) 287 - 291 2019.08

Research paper (scientific journal), Accepted, ISSN 13474367

© 2019 Activated charcoal is known to decrease the intestinal absorption of co-administered drug by adsorption. The extent of this drug-drug interaction (DDI) is attenuated by food intake. The aim of this study was to quantitatively evaluate the effects of food type on the extent of DDI between phenobarbital and activated charcoal using a rat model. Phenobarbital was orally administered at a dose of 1.5 mg/kg with or without 33 mg/kg of activated charcoal under fasted or fed conditions, and the plasma concentration profile of phenobarbital was monitored. Several fed conditions, such as a standard breakfast, high-fat meal or enteral nutrient used in human studies, were examined. Under the fasted conditions, activated charcoal significantly decreased the area under the plasma concentration - time curve (AUC) of phenobarbital by 45.2%. When the standard breakfast or high-fat meal was fed, this DDI was reduced to 28.3 and 18.0%, respectively, as assessed by the reduction in the AUC. On the contrary, enteral nutrient did not significantly attenuate the DDI. In conclusion, the influence of food intake on the extent of DDI between phenobarbital and activated charcoal was found to differ among the types of food concomitantly ingested.

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Inhibitory kinetics of fruit components on CYP2C19 activity

SEKI Hiroyuki, AKIYOSHI Takeshi, IMAOKA Ayuko, OHTANI Hisakazu

Drug Metabol. Pharmacokinet. (Drug Metabolism and Pharmacokinetics) 34 ( 3 ) in press, - 186 2019

Research paper (scientific journal), Joint Work, Accepted, ISSN 13474367

It has been suggested that the fruit components resveratrol (RSV), 6 ́,
7 ́-dihydroxybergamottin (DHB), and bergamottin (BG) might inhibit cytochrome P450 2C19 (CYP2C19) activity, but the mode and potency of such inhibition are yet to be investigated. This study aimed to investigate the mode and kinetics of the inhibition of CYP2C19-based omeprazole metabolism by RSV or grapefruit juice components (DHB or BG). RSV and DHB reduced CYP2C19 activity in a preincubation time-dependent manner, suggesting that they inactivated CYP2C19 via mechanism-based inhibition (MBI). Although BG inactivated CYP2C19 in a preincubation time- and concentration-dependent manner, suggesting that both MBI and reversible inhibition contributed to these effects, the concentration required to achieve 50% inhibition was 26-fold higher for reversible inhibition than for MBI (0.859 and 0.0331 μM, respectively), indicating that the inhibition of CYP2C19 by BG is primarily attributable to MBI. Based on the estimated intestinal concentrations of these components, it is considered that >90% of CYP2C19 would be inactivated after the consumption of normal amounts of grapefruit juice or RSV-containing substances. In conclusion, these findings suggest that food containing these components has the potential to evoke drug-food interactions caused by the MBI of intestinal CYP2C19 activity in the clinical setting.

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Food intake attenuates the drug interaction between new quinolones and aluminum.

IMAOKA Ayuko, ABIRU Kosuke, AKIYOSHI Takeshi, OHTANI Hisakazu

J Pharm Health Care Sci (BMC) 4 ( 11 ) 11 2018.05

Research paper (scientific journal), Joint Work, Accepted, ISSN 2055-0294

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The extent of drug-drug interaction between amlodipine and activated charcoal is attenuated by food intake in rats.

IMAOKA Ayuko, SEKI Kohei, AKIYOSHI Takeshi, OHTANI Hisakazu

Drug Metabol Pharmacokinet (Elsevier) 34 ( 1 ) [Epub ahead of print] - 110 2018

Research paper (scientific journal), Joint Work, Accepted, ISSN 13474367

Activated charcoal decreases gastrointestinal absorption of concomitantly administered drugs. The absorption of amlodipine (AML) was reported as almost completely attenuated by 25 g of activated charcoal under a fasted condition, but not affected by 2 g of activated charcoal under a fed condition. However, it is not clear whether this difference resulted from the food intake or the dose of activated charcoal. The aim of this study was to quantitatively evaluate the effect of food intake on drug interactions caused by adsorption to activated charcoal in the gastrointestinal tract in rats. The rats were orally administered 0.08 mg/kg of AML, with or without 33 mg/kg of activated charcoal, under the fasted or fed condition and the plasma concentration profiles of AML were monitored. For the fed group, the standard breakfast used in clinical studies was smashed and administered at a dose of 11 g/kg. The AUC value of AML under the fasted condition was significantly decreased to 24.8% by coadministration of activated charcoal. On the other hand, activated charcoal moderately decreased the AUC value of AML to 74.8% under the fed condition. These results suggest that the extent of drug interactions caused by activated charcoal is attenuated by food intake.

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5-Fluororacil-induced gastrointestinal damage impairs the absorption and anticoagulant effects of dabigatran etexilate.

TSUJII Kazunari, HATTORI Tomoki, IMAOKA Ayuko, AKIYOSHI Takeshi, OHTANI Hisakazu

J Pharm Sci (Wiley) 107 ( 5 ) 1430 - 1433 2018

Research paper (scientific journal), Joint Work, Accepted, ISSN 00223549

© 2018 American Pharmacists Association® Fluoropyrimidines, including 5-fluororacil (5-FU), cause gastrointestinal damage in the clinical setting and might affect the gastrointestinal absorption of concomitantly administered drugs. We aimed to evaluate the effects of fluoropyrimidine-induced gastrointestinal damage on the pharmacokinetics and pharmacodynamics of dabigatran etexilate (DABE), an anticoagulant, in rats with gastrointestinal damage induced by the repeated oral administration of 5-FU. Rats were administered DABE orally or dabigatran (DAB), an active moiety of DABE, intravenously. The plasma DAB concentration was determined using liquid chromatography-tandem mass spectrometry. The activated partial thromboplastin time (APTT) was measured before and 30 min after the administration of each drug, and the APTT ratio was calculated. In 5-FU-treated rats, the maximum plasma concentration, the area under the concentration-time curve of DAB after the oral administration of DABE, and the oral bioavailability of DABE were significantly decreased to 18.3%, 22.9%, and 16.3% of the respective control values. The 5-FU-treated rats’ APTT ratio was also significantly lower than the control value. Fluoropyrimidine-induced gastrointestinal damage might reduce the plasma concentration of DAB by impairing DABE absorption and might attenuate the anticoagulant effects of DABE in the clinical setting.

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Development of a New Scholastic Program for Medication Counseling Practice in Preclinical Training, Constructed for Junior Students by Senior Students Based on Their Experiences of On-site Practice

SUZUKI Sayo, AONO Izumi, IMAI Natsumi, KAWABATA Aki, KENDA Yuki, MATSUMOTO Minako, YOSHIDA Aya, WATANABE Asuka, TAKAGI Akinori, KOBAYASHI Noriko, SAEKI Haruko, OHTANI Hisakazu, NAKAMURA Tomonori, KIZU Junko

YAKUGAKU ZASSHI (Yakugaku Zasshi) 137 ( 11 ) 1391 - 1408 2017.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 00316903

Long-term practical on-site training, based on the Model Core Curriculum for Pharmaceutical Education, is a core program of the 6-year course of pharmaceutical education, introduced in Japan in 2010. In particular, medication counseling in practical training in 5th-year provides valuable opportunities for communication with real patients rather than simulated patients (SPs). However, it can also cause anxiety in 4th-year students before practical training. To address such concerns, upperclassmen (5th-and 6th-year students), who have already completed practical training, constructed and conducted a new educational program for medication counseling practice in preclinical training based on their experiences. They also developed case scenarios and played the role of patients themselves to create more realistic clinical settings. Advice from professional SPs was also provided. The 5-step program is composed of 1st counseling, 1st small group discussion (SGD) for improving counseling, 2nd revised counseling based on the 1st SGD, 2nd SGD, and development of a counseling plan and presentation. Educational effects of the program were evaluated by questionnaire survey after preclinical training in 4th-year students and after their practical training in 5th-year students. This new program, the Advanced Medication Counseling Practice, was found to be useful to reduce anxiety about communication with patients among 4th-year students (about 90%). Even after their practical training in 5th-year, they still appreciated usefulness of this program (about 80%). This program is still valued 4 years after its development. We developed the Advanced Medication Counseling Practice in preclinical training for junior students by senior students.

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Inactivation kinetics and residual activity of CYP3A4 after treatment with erythromycin.

ISHIKAWA Yuko, AKIYOSHI Takeshi, IMAOKA Ayuko, OHTANI Hisakazu

Biopharm Drug Dispos (WILEY) 38 ( 7 ) 420 - 425 2017.07

Research paper (scientific journal), Joint Work, Accepted, ISSN 01422782

This study aimed to characterize the inactivation kinetics of cytochrome P450 3A4 (CYP3A4) by erythromycin, which involves mechanism-based inhibition (MBI), in detail. In addition to an MBI assay based on the conventional method in which erythromycin and recombinant CYP3A4 were pre-incubated for 15 min, the study also evaluated the long-term MBI kinetics of this reaction by pre-incubation for 120 min. Mechanism-based inhibition profiles were obtained using three typical substrates, testosterone, midazolam and nifedipine. In the long-term assay, erythromycin evoked a time-dependent biphasic reduction in enzyme activity, but some residual activity (α) was detected in the terminal phase. The inactivation rate constant obtained in the presence of 30 μm erythromycin using nifedipine as a substrate was 1.44-fold higher than that acquired using testosterone, while there was no difference among the α values obtained with the three substrates. In the short-term assay, time-dependent monophasic inactivation was observed. To extrapolate these data to in vivo, the extent of the increase in the area under the curve (AUC ratio) induced by erythromycin was estimated from the results of the conventional short-term experiment and the long-term experiment examining residual activity. The AUC ratio estimated from the long-term kinetics (2.92) was closer to the clinically reported values (3.3–4.42). In conclusion, the relatively long-term evaluation of the kinetics of CYP3A4 inactivation revealed that the enzyme was not fully inactivated by erythromycin. To improve the estimation of the extent of the drug–drug interactions induced by MBI from in vitro data, longer-term investigations of the target enzyme's inactivation profile might be necessary.

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Development and evaluation of an overseas clinical rotation program for undergraduate pharmacy students in Japan

OHTANI Hisakazu, MITSUI Rieko, AKIYOSHI Takeshi, IMAOKA Ayuko, ABE Yoshihiro, KANKE Motoko, NAKAMURA Tomonori, FOSTER Patrick, MOCHIZUKI Mayumi

Currents in Pharmacy Teaching and Learning (Elsevier) 9 ( 3 ) 452 - 459 2017

Research paper (scientific journal), Joint Work, Accepted, ISSN 18771297

Background and purpose Internationalization of pharmacists, as well as pharmacy students, in terms of both the knowledge to care for international patients and to have medical information literacy, is a current concern in Japan. Educational activity and setting Keio University Faculty of Pharmacy has developed an elective course for pharmacy students, based on written agreements with the United States and Thailand that establish a student clinical rotation exchange program. The exchange program lasts for four to six weeks and involves clinical rotations in hospitals abroad during the students’ sixth year. Rotations follow a four-week didactic preparatory course. The course objectives are to acquire the knowledge, skills, and attitude needed to function as leading pharmacists with an international perspective. Methods We asked students to complete a feedback survey inquiring about the usefulness of preparatory courses, self-evaluation pre- and post-rotation satisfaction with the program, and overall self-assessment. Findings Twenty-four out of 41, i.e., 58.5% of the students replied with feedback. All respondents replied that the preparatory course was useful. They also replied that, based on their self-evaluation, they were satisfied with their level of English language skill improvement after the rotation. Pharmaceutical knowledge satisfaction, however, was slightly decreased. All respondents replied that this program was of a satisfactory nature, with 71%, 63%, and 92% of the respondents replying that they could acquire the knowledge, skills, and attitude program objectives respectively. Summary It is possible to successfully develop an overseas clinical rotation program. Students were quite satisfied upon completion and achieved the expected objectives.

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5-Fluorouracil treatment alters the expression of intestinal transporters in rats.

YOTSUMOTO Keiichi, AKIYOSHI Takeshi, WADA Naoki, IMAOKA Ayuko, OHTANI Hisakazu

Biopharm Drug Dispos (Biopharmaceutics and Drug Disposition) 38 ( 9 ) 509 - 516 2017

Research paper (scientific journal), Joint Work, Accepted, ISSN 01422782

5-Fluorouracil (5-FU), an anticancer drug, causes severe gastrointestinal damage, which may affect the absorption of orally administered drugs including the substrates of intestinal uptake and efflux transporters. This study aimed to investigate quantitatively the effect of 5-FU-induced intestinal damage on the expression of intestinal transporters: P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and peptide transporter 1 (PEPT1) in rats. The rats were treated with 5-FU (30 mg/kg/day, p.o.) for 5 days to induce intestinal damage, and then the upper, middle and lower intestinal segments were removed. The mRNA and protein expression levels of these transporters in each segment were determined using quantitative real-time PCR and Western blotting, respectively. In the 5-FU-treated rats, the protein levels of P-gp and Bcrp in the upper segment were significantly increased to 15- and 2.6-fold of the control, respectively, while those in other segments were unaffected. Pept1 expression was increased by 5-FU in almost all segments. A remarkable increase in P-gp expression was shown, the uptake of digoxin, a P-gp substrate, in each intestinal segment was measured using a rat everted sac. As a result, the uptake of digoxin in the upper segments of 5-FU-treated rats was decreased compared with that of the control. In conclusion, 5-FU-induced intestinal damage was shown to alter the expression of these transporters, especially in the upper intestinal segment, while the characteristics of the influence varied among the transporters. The 5-FU-induced intestinal damage may affect transporter-mediated drug absorption of orally administered drugs in the clinical setting.

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Analysis of the mechanism of prolonged persistence of drug interaction between terbinafine and amitriptyline or nortriptyline.

MIKAMI Akiko, HORI Satoko, OHTANI Hisakazu, SAWADA Yasufumi

Biol Pharm Bull (Biological and Pharmaceutical Bulletin) 40 ( 7 ) 1010 - 1020 2017

Research paper (scientific journal), Joint Work, Accepted, ISSN 09186158

The purpose of the study was to quantitatively estimate and predict drug interactions between terbinafine and tricyclic antidepressants (TCAs), amitriptyline or nortriptyline, based on in vitro studies. Inhibition of TCA-metabolizing activity by terbinafine was investigated using human liver microsomes. Based on the unbound Ki values obtained in vitro and reported pharmacokinetic parameters, a pharmacokinetic model of drug interaction was fitted to the reported plasma concentration profiles of TCAs administered concomitantly with terbinafine to obtain the drug–drug interaction parameters. Then, the model was used to predict nortriptyline plasma concentration with concomitant administration of terbinafine and changes of area under the curve (AUC) of nortriptyline after cessation of terbinafine. The CYP2D6 inhibitory potency of terbinafine was unaffected by preincubation, so the inhibition seems to be reversible. Terbinafine competitively inhibited amitriptyline or nortriptyline E-10-hydroxylation, with unbound Ki values of 13.7 and 12.4 nM, respectively. Observed plasma concentrations of TCAs administered concomitantly with terbinafine were successfully simulated with the drug interaction model using the in vitro parameters. Model-predicted nortriptyline plasma concentration after concomitant nortriptylene/terbinafine administration for two weeks exceeded the toxic level, and drug interaction was predicted to be prolonged; the AUC of nortriptyline was predicted to be increased by 2.5- or 2.0- and 1.5-fold at 0, 3 and 6 months after cessation of terbinafine, respectively. The developed model enables us to quantitatively predict the prolonged drug interaction between terbinafine and TCAs. The model should be helpful for clinical management of terbinafine-CYP2D6 substrate drug interactions, which are difficult to predict due to their time-dependency.

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P450を介した薬物相互作用に個人差をもたらす遺伝的要因の定量的解明と予測

秋好健志, 大谷壽一, 今岡鮎子

臨床薬理の進歩 ((公財)臨床薬理研究振興財団) ( 37 ) 128 - 135 2016.06

ISSN 0914-4366

CYP2D6の代謝活性に対するテルビナフィン(TER)の阻害に関して、時間依存性の有無を明らかにするとともに、その阻害特性に対するCYP2D6遺伝子変異の影響を解析した。TERの競合阻害実験において、全てのCYP2D6変異型分子の代謝活性は、TERの濃度依存的に低下した。一方、CYP2D6の各変異型分子に対するTERの時間依存的な酵素活性阻害作用は認められなかった。CYP2D6に対するTERの阻害メカニズムは、競合阻害作用のみが関与していることが示唆された。TERが示す長時間持続阻害作用は、時間依存性ではなく、TER自身の消失の遅さに起因すると考えられた。また、TERによる阻害に対するCYP2D6の感受性は各変異型分子間で大きく異なっていたことから、TERによるCYP2D6の阻害を介した薬物相互作用を考慮する際には、CYP2D6の遺伝子型を考慮する必要があると考えられた。

In silico evaluation of warfarin-bucolome therapy.

OHTANI Hisakazu,Ryoko Hakoda, Ayuko Imaoka, Takeshi Akiyoshi

Biopharm Drug Dispos (Wiley) 37 233 - 242 2016

Research paper (scientific journal), Joint Work, Accepted

In silico evaluation of warfarin–bucolome therapy

Ohtani H., Hakoda R., Imaoka A., Akiyoshi T.

Biopharmaceutics and Drug Disposition (Biopharmaceutics and Drug Disposition) 37 ( 4 ) 233 - 242 2016

ISSN 01422782

Purpose: Some reports have suggested that bucolome, an inhibitor of cytochrome P450 2C9, is useful for decreasing inter-patient variation in warfarin clearance. The purpose of the present study was to evaluate the utility of the concomitant administration of bucolome and warfarin using an in silico approach. Methods: In vitro data regarding the enzymatic kinetics of (S)-warfarin and bucolome were collected from the literature. As a validation study, the geometric mean (GM) of the oral unbound clearance of (S)-warfarin and its inter-patient variation (assessed using the standard deviation of its natural logarithm (σ)) were predicted using a physiologically based population pharmacokinetic simulator (SimcypTM) and compared with clinical data. The utility of the concomitant administration was evaluated by comparing the GM and σ values predicted under various conditions (the prediction study). Results and Discussion: The σ values in the presence and absence of bucolome were predicted to be 0.73 and 0.68, respectively, suggesting that bucolome might increase the inter-patient variation, as clinically observed. In the prediction study, the σ value of the bucolome co-administered group was greater in almost all of the examined conditions. In conclusion, the concomitant administration of bucolome might not be useful for reducing the inter-patient variation of (S)-warfarin pharmacokinetics. Copyright © 2016 John Wiley & Sons, Ltd.

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Estimation of the Dose-Dependency of Systemic Adverse Drug Reactions during the Subtherapeutic Administration of Various Drugs

MITSUI Rieko, AKIYOSHI Takeshi, IMAOKA Ayuko, MOCHIZUKI Mayumi, OHTANI Hisakazu

Jpn J Drug Inform (JASDI) 17 ( 2 ) 77 - 86 2015.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 1345-1464

常用量以下の曝露量における全身性副作用の用量依存性について検討した。解析対象薬物として、常用量製剤に加えて、低曝露製剤として、貼付剤、点眼薬などといった局所適用製剤、あるいは低用量の経皮剤などといった全身曝露量の少ない全身作用型製剤が使用されている薬物を選択した。NSAIDsは、常用量製剤が27成分、低曝露製剤が17成分が上市され、常用量製剤と低曝露製剤の療法が上市されているのは10成分であった。β-ブロッカーでは、常用量製剤が22成分、低曝露製剤が7成分あり、両製剤が上市されているのは5成分であった。免疫抑制剤・ステロイドでは、常用量製剤が10成分、低曝露製剤が17成分あり、両製剤が上市されているのは5成分であった。AUCが常用量製剤の概ね20%以上では全身性副作用の発現は明らかであり無視できず、概ね3〜20%程度の曝露でも、減少はするものの完全には消失しないことが示唆された。

Variation in the inhibitory potency of terbinafine among genetic variants of CYP2D6

AKIYOSHI Takeshi, ISHIUCHI Miho, IMAOKA Ayuko, OHTANI Hisakazu

Drug Metabolism and Pharmacokinetics (Drug Metabolism and Pharmacokinetics) 30 ( 4 ) 321 - 324 2015.04

Research paper (scientific journal), Joint Work, Accepted, ISSN 13474367

Cytochrome P450 2D6 (CYP2D6) is a highly polymorphic enzyme that is involved in the metabolism of many drugs. Terbinafine (TER) is a CYP2D6 inhibitor and causes persistent drug interactions in the clinical setting; however, its inhibitory mechanism and the differences in its inhibitory potency among genetic variants of CYP2D6 remain to be investigated. This study aimed to investigate the inhibitory mechanism of TER and the differences in its inhibitory potency among three CYP2D6 variants, CYP2D6.1, CYP2D6.2, and CYP2D6.10. In a competitive inhibition study, the metabolic activity of the CYP2D6 was assessed based on their demethylation of dextromethorphan in the presence or absence of TER, and the time-dependency of the inhibitory effects were examined by preincubating the enzymes with TER. TER had weaker inhibitory effects on CYP2D6.2 and CYP2D6.10 than on CYP2D6.1; i.e., TER exhibited Ki values (the concentration of inhibitor that results in half-maximal inhibition) of 0.0525, 0.355, and 1.85 μM for CYP2D6.1, CYP2D6.2, and CYP2D6.10, respectively. The inhibitory effects of TER were not time-dependent. Since TER's Ki value for CYP2D6.10 was 35.2-fold higher than its Ki value for CYP2D6.1, the CYP2D6 genotype of subjects should be taken into account when estimating the severity of drug interactions involving TER.

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Current state of the illegal trading of pharmaceutical products on internet auction sites in Japan and the responses of site administrators to such transactions

Ohtani H*, Imaoka A, Akiyoshi T.

YAKUGAKU ZASSHI (Yakugaku Zasshi) 135 ( 3 ) 529 - 534 2015.02

Research paper (scientific journal), Joint Work, Accepted, ISSN 00316903

In Japan, it is illegal to sell pharmaceuticals on Internet auction sites, although a considerable number of pharmaceuticals are listed on such sites. We investigated the current situation regarding the illegal trade in pharmaceuticals on Japanese Internet auction sites and the responses of site administrators to such transactions. We searched for pharmaceuticals and ``gray'' items that were suspected of being pharmaceuticals on Yahoo-oku! (Yahoo! Auctions, Japan) over a 37-day period and then submitted violation reports indicating that selling pharmaceuticals is illegal or that the description of an item was insufficient. The reports were directed to the site administrators and forwarded to the sellers. One hundred and six pharmaceutical products and 34 gray items were identified during the study period. After the submission of the violation reports, only 28 of the pharmaceutical products and one of the gray items were deleted by the administrator, while 18 of the pharmaceutical products and 7 of the gray items were withdrawn by their sellers. However, 41 pharmaceuticals and 20 gray items were sold. Most of the gray items were listed using characteristic terms or abbreviations without photographic images. More than 70％ of the identified pharmaceuticals had a contraindication (s) other than hypersensitivity. In conclusion, the illegal trade in pharmaceuticals on Internet auction sites remains a serious problem in Japan, and the responses of site administrators to such transactions are inadequate. The government and pharmaceutical industry may have to take measures such as providing public and administrative guidance to stop the illegal trade in pharmaceuticals on the Internet.

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Inhibitory effects and structure-activity relationship of flavonoids with respect to human organic aniontransporting polypeptides, OATP2B1

SATOH Hiroki, FUCHIKAMI Hiromi, OHTANI Hisakazu, TSUJIMOTO Masayuki, OHDO Shigehiro, SAWADA Yasufumi

Intl J Pharm Phytopharmacol Res 5 ( 3 ) 33 - 40 2015

Research paper (scientific journal), Joint Work, Accepted, ISSN 2250-1029

Prediction of the extent and variation of grapefruit juice-drug interactions from the pharmacokinetic profile in the absence of grapefruit juice."

Kogure N, Akiyoshi T, Imaoka A, Ohtani H*.

Biopharmaceutics & Drug Disposition (Biopharmaceutics and Drug Disposition) 35 ( 7 ) 373 - 381 2014.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 01422782

The aim of this study was to develop a method for predicting the extent of grapefruit juice (GFJ)-drug interactions and their interindividual variations from the pharmacokinetic profile in the absence of GFJ. The pharmacokinetic profiles of 13 drugs after intravenous and oral administration were used to develop and validate the method. For each drug, the proportion absorbed into the intestine and the intestinal availability (Fg) were calculated from clinical data taken from the literature. Then, the AUC ratio (the ratio of the AUC with GFJ to that without GFJ) was predicted by assuming that Fg was 1.0 when GFJ was concomitantly ingested. According to the developed method, the AUC ratio of felodipine was 2.50 and its coefficient of variation (CV) was 45%, which agreed well with the observed AUC ratio of 2.48 and CV of 51%. Although the developed method overestimated the AUC ratios of some drugs such as nisoldipine, no underestimation occurred. The predicted CV values were consistent with those observed. The developed method might be useful to predict the AUC ratio, along with its interindividual variation, from the pharmacokinetic profile in the absence of grapefruit juice.

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Decrease in ciprofloxacin absorption by polyvalent metal cations is not fully attributable to chelation or adsorption.

Imaoka A, Hattori M, Akiyoshi T, Ohtani H*.

Drug Metabolism and Pharmacokinetics (Drug Metabolism and Pharmacokinetics) 29 ( 5 ) 414 - 418 2014.05

Research paper (scientific journal), Joint Work, Accepted, ISSN 1347-4367

The drug interaction between new quinolone antibiotics (NQs) and polyvalent metal cation products, leading to a significant decrease in the absorption of NQ, is considered to be attributable to the formation of poorly absorbable chelate and physicochemical adsorption of NQs to cation products. To clarify the mechanisms of this drug interaction in detail, we investigated the effects of Al3+ or Mg2+ on the membrane permeation profile of ciprofloxacin (CPFX) across human colon carcinoma cell lines (Caco-2) in monolayer culture, and characterized the adsorption nature of CPFX to polyvalent metal cation products under physiological conditions. As a result, Al3+ or Mg2+ partially but not fully impaired the permeation of CPFX across Caco-2 monolayer up to 30% or 60% of control, respectively. Physicochemical adsorption of CPFX to cation products was not observed under physiological pH. In conclusion, two possible mechanisms investigated, the decrease in the permeability of CPFX by chelate formation and adsorption of CPFX to polyvalent metal cation products, may partially but not fully explain the extent of the drug interaction clinically observed.

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OTC薬実習の問題点とその改善のための提案.

剱田侑希, 門田佳子, 鈴木小夜, 青森達, 小林典子, 高木彰紀, 手塚淑人, 大谷壽一, 中村智徳*.

医療薬学 ((一社)日本医療薬学会) 40 ( 2 ) 117-123 - 123 2014.02

Research paper (scientific journal), Joint Work, Accepted, ISSN 1346-342X

平成24年度薬局実務実習を終了した大学薬学部5年生を対象にアンケート調査を行い一般用医薬品(over-the-counter drug、OTC薬)実習改善のための方策について検討した。全体集計には回収分(158名、回収率94.6%)を使用し、記入漏れのない回答を有効回答とし、統計解析により有効回答(152名、有効回答率91.0%)のみを使用した。薬局OTC薬実習において27.8%(44名)の学生が来局者に対し、販売することができ、18.4%(29名)の学生が相談販売を行うことができた。相談販売を行った学生の中には指名販売を含めると50回以上販売できた学生が2名いた。一方で、販売、ロールプレイ(RP)、OTC薬販売の見学など、演習形式の実習のいずれも実施しない学生が11.4%(18名)いた。OTC薬実習に対する学生の「興味」「十分な実施」「満足度」に関しては実施状況による差がみられた。

Characterization of transplacental transfer of paroxetine in perfused human placenta: development of a pharmacokinetic model to evaluate tapered dosing.

Nagai M, Ohtani H, Satoh H, Matsuoka S, Hori S, Fujii T, Taketani Y, Sawada Y*.

Drug Metabol Dispos (Drug Metabolism and Disposition) 41 ( 12 ) 2124 - 2132 2013.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 00909556

The aim of this study was to determine whether a tapered dosage regimen of paroxetine in pregnant women might be useful to avoid withdrawal syndromes in neonates after delivery. We characterized the transplacental transfer of paroxetine in perfused human placenta, fitting a pharmacokinetic model to the results and applying the model and parameters to evaluate a tapered dosage regimen. Paroxetine was perfused from the maternal or fetal side of an isolated human placental preparation with various perfusion protocols, and paroxetine concentrations in the effluent and placental tissue were determined. The transplacental pharmacokinetic parameters of paroxetine were estimated by simultaneous fitting of a five-compartment transplacental pharmacokinetic model to the set of paroxetine concentration profiles. The developed model and parameters were used to simulate the maternal and fetal concentrations of paroxetine, and the results were compared with reported data. Paroxetine showed a larger distribution volume in placental tissue and a smaller transplacental transfer as compared with antipyrine, a passive diffusion marker. A five-compartment model could well describe the transplacental transfer of paroxetine and could well simulate the maternal and umbilical venous concentrations of paroxetine at delivery. Transplacental transfer kinetic parameters of paroxetine were estimated by fitting a pharmacokinetic model to perfusion study data. The model and parameters appeared to be suitable for simulation of paroxetine kinetics in fetus. The model was also applicable to design a dosage regimen to avoid an abrupt decrease of paroxetine concentration in fetal plasma. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics.

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Effect of aromatase inhibitors on bone mineral density in Japanese breast cancer population.

Akiyoshi T, Shimomura Y, Masuda S, Okamoto Y, Hiura S, Kato H, Asayama T, Ohtani H*.

Drug Metabol Pharmacokinet (Drug Metabolism and Pharmacokinetics) 25 ( 5 ) 446 - 450 2013.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 13474367

We retrospectively analyzed the bone mineral density (BMD) of postmenopausal Japanese women taking an aromatase inhibitor (AI), exemestane, anastrozole or letrozole, and calculated the decrease rate constant of BMD in each individual to compare the influence of the three AIs on BMD. We also aimed to evaluate the preventive effect of bisphosphonates (BPs) on the AI-induced decrease in BMD. The decrease rate constant of BMD (ke) in each individual was determined as a slope of linear regression of the relationship between time and logarithm of BMD value in each patient during the AI therapy. To compensate for the age-related change in BMD level, we estimated the age-related decrease rate constant of BMD (ke,0) in healthy Japanese postmenopausal women from the literature. AIs decreased BMD with a ke value of -0.0329 yr-1, which was 4.7-fold larger than the ke,0 value of -0.00699 yr-1. No significant difference was detected in the influence on BMD among AIs. Co-administration of BP ameliorated the ke value to -0.0117 yr-1, a value similar to ke,0. The influence of AIs on BMD was quantitatively evaluated by using the decrease rate constant of BMD (ke). The present study also suggests that BPs may be useful to prevent the decrease in BMD induced by AIs. © 2013 by the Japanese Society for the Study of Xenobiotics (JSSX).

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Mechanism-based inhibition profiles of erythromycin and clarithromycin with cytochrome P450 3A4 genetic variants.

Akiyoshi T, Ito M, Murase S, Miyazaki M, Guengerich F, Nakamura K, Yamamoto K, Ohtani H*.

Drug Metabol Pharmacokinet (Drug Metabolism and Pharmacokinetics) 25(5) ( 5 ) 411 - 415 2013.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 13474367

Inhibition of cytochrome P450 (CYP) 3A4 is the major cause of drug-drug interactions (DDI). We have previously reported that the genetic variation of CYP3A4 significantly affected the inhibitory profiles of typical competitive inhibitors. In addition to competitive inhibition, some clinically significant DDI are attributable to mechanism-based inhibition (MBI). However, the differences in the MBI kinetics among CYP3A4 genetic variants remain to be characterized. In this study, we quantitatively investigated the inhibition kinetics of MBI inhibitors, erythromycin and clarithromycin, on the CYP3A4 variants CYP3A4.1, 4.2, 4.7, 4.16, and 4.18. The activity of CYP3A4 was assessed using testosterone 6β-hydroxylation with recombinant CYP3A4. Both erythromycin and clarithromycin decreased the activity of CYP3A4 in a timedependent manner. The maximum inactivation rate constants, kinact,max, of erythromycin for CYP3A4.2 and CYP3A4.7 were 0.5-fold that for CYP3A4.1, while that for CYP3A4.16 and CYP3A4.18 were similar to that for CYP3A4.1. The KI values of erythromycin for CYP3A4.2, 4.7, 4.16, and 4.18 were 1.2-, 0.4-, 2.2- and 0.72-fold those of CYP3A4.1, respectively. Similar results were obtained for clarithromycin. In conclusion, the inhibitory profiles of MBI inhibitors, as well as competitive inhibitors, may possibly differ among CYP3A4 variants. This difference may contribute to interindividual differences in the extent of DDI based on MBI. © 2013 by the Japanese Society for the Study of Xenobiotics (JSSX).

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Pharmacokinetic model incorporating mechanism-based inactivation of CYP2D6 can explain both non-linear kinetics and drug interactions of paroxetine.

Mikami A, Ohtani H, Hori S, Sawada Y*.

Int J Clin Pharmacol Ther (International Journal of Clinical Pharmacology and Therapeutics) 51(5) ( 5 ) 374-382 - 382 2013.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 09461965

Objective: To develop a pharmacokinetic model able to describe the nonlinear pharmacokinetics of paroxetine (PRX) and to predict the drug-drug interaction between PRX and metoprolol under various dosage regimens. Methods: A pharmacokinetic model of PRX incorporating mechanism-based inhibition was developed. This model was fitted to the drug concentration profiles obtained after single and repeated administrations of PRX to estimate the pharmacokinetic parameters of PRX and degradation rate constant of cytochrome P450 (CYP) 2D6. It was also fitted to the time profile of S-metoprolol after coadministration of metoprolol and PRX, and the fractional contribution of CYP2D6 to overall clearance of S-metoprolol was estimated. Using the developed model and estimated parameters, an optimal dosage regimen for metoprolol during withdrawal of PRX was simulated. Results: The developed model well described the time profiles of both PRX and metoprolol concentration during concomitant administration. The estimated parameters were consistent with reported values. The nonlinear and accumulation properties of PRX could be explained by mechanism-based inhibition of CYP2D6 by PRX. Upon tapering PRX from 20 mg/day to 10 mg/day for 14 days then 5 mg/day for 14 days until cessation, the optimal dosage regimen to resume 120 mg/day of metoprolol based on the developed model was as follows: 30 mg/day during concomitant administration, 40 mg/day for the next 14 days, 60 mg/day for the next 14 days, and finally 120 mg/day. Conclusions: The developed model enabled us to quantitatively estimate drug-drug interactions of PRX and CYP2D6 substrate drugs, and to predict optimal dosage regimens. © 2013 Dustri-Verlag Dr. K. Feistle ISSN 0946-1965.

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Stability of the admixture of trace elements and vitamin-containing TPN solution in a multi-chamber bag (Fulcaliq).

Okuyama Y, Akiyoshi T, Asayama T, Hirai M, Matsuyama K Ohtani H* .

The Journal of Asian Association of Schools of Pharmacy 1(3) 152-158 2012.09

Research paper (scientific journal), Joint Work, Accepted

Prediction and evaluation of fetal toxicity induced by NSAIDs using transplacental kinetic parameters obtained from human placental perfusion studies.

Shintaku K, Hori S, Satoh H, Tsukimori K, Nakano H, Fujii T, Taketani Y, Ohtani H, Sawada Y*.

Br J Clin Pharmacol (British Journal of Clinical Pharmacology) 73(2) ( 2 ) 248-256 - 256 2012.02

Research paper (scientific journal), Joint Work, Accepted, ISSN 03065251

Aim: The use of nonsteroidal anti-inflammatory drugs (NSAIDs) in full-term pregnant women leads to fetal or neonatal toxicity, such as constriction of the ductus arteriosus (DA) and persistent pulmonary hypertension in the newborn. The aim of this study was to predict quantitatively the fetal toxicity of three NSAIDs (antipyrine, salicylic acid and diclofenac) using the transplacental pharmacokinetic parameters obtained from our previous placental perfusion studies. Methods Human fetal plasma concentration profile after oral administration of each NSAID to the mother was estimated using the transplacental pharmacokinetic parameters and pharmacokinetic parameters in adult women. The fetal plasma concentration-response relationship for the three NSAIDs was estimated by pharmacokinetic/pharmacodynamic analysis of the results of previous studies investigating the effects of NSAIDs on the ratio of inner diameter of the DA to that of the pulmonary artery (DA/PA) in rats and the plasma concentration profiles of NSAIDs in pregnant rats. Results The risk of constriction of the DA was well predicted by the model. Mean DA/PA ratio after oral administration of diclofenac to the mother was estimated to be 39.0%, whereas both of the corresponding values after oral administration of antipyrine and salicylic acid were estimated to be 5.9%. These results suggest that the fetal risk of diclofenac is higher than those of salicylic acid and antipyrine. Conclusions This study presents a novel approach to predict quantitatively the fetal risk of NSAIDs administered to the mother. Human placental perfusion study and pharmacokinetic/pharmacodynamic analysis may provide basic data for predicting human fetal toxicity of drugs. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

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Warfarin and miconazole oral gel interactions: Analysis and therapy recommendations based on clinical data and a pharmacokinetic model

Miki A., Ohtani H., Sawada Y.

Journal of Clinical Pharmacy and Therapeutics (Journal of Clinical Pharmacy and Therapeutics) 36 ( 6 ) 642 - 650 2011.12

ISSN 02694727

Summary What is known and Objective: Miconazole is a strong inhibitor of CYP2C9, one of the main enzymes involved in the metabolism of warfarin. Concurrent use of the two drugs leads to potentially serious adverse effects. Although it is often assumed that use of the oral miconazole gel is acceptable with concomitant warfarin, because of the low bioavailability following buccal administration, drug-drug interactions have been reported following such use. We aimed to investigate case reports of such interactions and develop a pharmacokinetic model to model such interactions. Methods: The Medline database from 1966 to October 2010 was used for literature search. Case reports of the potentiation of the anticoagulant effects of warfarin, such as the elevation of prothrombin time (INR), by concomitant administration of warfarin and miconazole oral gel were collected. We quantitatively estimated the extent of inhibition of warfarin metabolism by orally administered miconazole gel and compared our findings with case reports. Results and Discussion: Metabolism of (S)-warfarin is inhibited potently following administration of a standard dose (200-400 mg/day in Japan) of miconazole gel. This may lead to in an increase in the blood concentration of warfarin and lead to serious adverse effects. The literature reports of clinical interactions with concomitant use of those drugs show that other factors may amplify the effects of any increase in blood concentration. What is new and Conclusion: We summarize all reported, clinically significant, cases of drug interaction between miconazole oral gel and warfarin. Pharmacokinetic modelling shows that concomitant administration of warfarin and miconazole oral gel can lead to substantial increase in warfarin concentration. However, our PK/PD model fails to capture the dramatic increases seen in INR values, and hence bleeding complications, reported in the literature. Taken together, the evidence suggests that concomitant use of miconazole gel and warfarin should be avoided. Even over-the-counter products containing miconazole should be used with caution by patients receiving warfarin. © 2010 Blackwell Publishing Ltd.

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Model analysis of tulobuterol patch formulations to explain the influence of drug release rate and transdermal transfer rate on the plasma concentration profile

Watanabe T., Satoh H., Hori S., Miki A., Ohtani H., Sawada Y.

Yakugaku Zasshi (Yakugaku Zasshi) 131 ( 10 ) 1483 - 1492 2011.10

ISSN 00316903

The purpose of this study was to compare the transdermal transfer profiles of brand and generic tulobuterol patch formulations and to evaluate possible changes of in vivo kinetics resulting from increased transdermal transfer by means of pharmacokinetic analysis using reported in vitro drug release rate data and plasma drug concentration profiles. On the assumption that the transdermal transfer rate constant (k2) would be constant (independent of formulation), the drug release rate constant from patch formulation (k1) was predicted to be almost equal to the k2 value (k1≈k2) in the brand formulation, but 2- to 4-fold higher than the k2 value (k1>k2) in the two generic formulations. Under normal conditions, there would be no marked difierence in the plasma concentration profiles among the formulations. However, under conditions where transdermal transfer is increased (that is, higher k2), the plasma tulobuterol concentration was predicted to increase more rapidly, with higher C max, and then to decrease more rapidly in the elimination phase after applying the generic formulations compared with the brand formulation. These difierent behaviors would be seen because the transdermal transfer of the generic formulations would be afiected by k2, whereas k1 is still rate-determining for the brand formulation. These results suggest that bronchial asthma patients with risk factors for impaired skin barrier function, including atopic dermatitis, long-term treatment with steroids, and advanced age, should be carefully monitored for reduced treatment efficacy or adverse drug reactions after application of rapid-release generic tulobuterol patch formulations. © 2011 The Pharmaceutical Society of Japan.

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Bottom-up modeling and simulation of tacrolimus clearance: Prospective investigation of blood cell distribution, sex and CYP3A5 expression as covariates and assessment of study power.

Ohtani H*, Barter Z, Minematsu T, Makuuchi M, Sawada Y, Rostami-Hodjegan A.

Biopharm Drug Dispos (Biopharmaceutics and Drug Disposition) 32(9) ( 9 ) 498-506 - 506 2011.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 01422782

The objectives were to investigate the ability of population-based in vitro-in vivo extrapolation (IVIVE) to reproduce the influence of haematocrit on the clearance of tacrolimus, observed previously, and to assess the power of clinical studies to detect the effects of covariates on the clearance of tacrolimus. A population-based pharmacokinetic simulator (Simcyp) was used to simulate tacrolimus clearance from in vitro metabolism data and demographic characteristics of Japanese liver transplant patients (JLTs). The relationship between haematocrit and dose-to-concentration (D/C) ratio was validated using seven JLTs, whose highly variable haematocrit and D/C ratio were previously analysed. This validation was used as a surrogate for establishing 'interindividual' variability and to assess the power of clinical studies to discern the effect of haematocrit, sex and CYP3A5 genotype on tacrolimus clearance in a virtual JLT population. The relationship between haematocrit and D/C ratio was reproducible by Simcyp and corresponded well to those observed in seven JLTs. The number of JLTs required to detect the influence of CYP3A5 genotype and sex were estimated to be about 50 and > 600, respectively, which was consistent with the results of previous population pharmacokinetic studies for tacrolimus. In conclusion, population-based IVIVE is considered to be a useful approach to assess the influence of covariates a priori before conducting clinical studies. This is also helpful with study design and assessment of the statistical power of clinical studies involving population-based pharmacokinetics to detect the effects of covariates. Copyright © 2011 John Wiley & Sons, Ltd.

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Model analysis of tulobuterol patch formulation to explain the influence of drug release rate and transdermal transfer rate on the plasma concentration profile.

Watanabe T, Satoh H, Hori S, Miki A, Ohtani H, Sawada Y*.

Yakugaku Zasshi 131(10) 1483-1492 2011.10

Research paper (scientific journal), Joint Work, Accepted

ツロブテロール貼付後の血漿中濃度に及ぼす製剤特性と皮膚透過性の影響に関する薬物動態学的解析

渡邉哲夫, 佐藤宏樹, 堀里子, 三木晶子, 大谷壽一, 澤田康文

薬学雑誌 ((公社)日本薬学会) 131 ( 10 ) 1483 - 1492 2011.10

ISSN 0031-6903

気管支喘息治療に適応をもつツロブテロールの全身作用型経皮吸収製剤であるホクナリンテープは、持続的な薬物放出制御システム(結晶レジンボアシステム)により、過度な血中濃度上昇を抑制することで全身性の副作用(振戦や心悸亢進など)を軽減し、さらに長時間作用を持続させることでモーニングディップ(早朝の喘息発作)を抑制することが示されている。ツロブテロール貼付剤にはホクナリンテープ以外にも複数の後発医薬品が承認されており、生物学的同等性試験により先発医薬品と同等であることが検証されている。しかし、後発医薬品では結晶レジンボアシステムは採用されておらず、ツロブテロールの放出がホクナリンに比べて速いことがin vitroの実験で示されている。臨床的にも、先発医薬品で喘息症状が良好にコントロールされていた患者が後発医薬品への切替え後に症状増悪した症例や副作用(振戦)が出現した症例が報告されている。そこで今回、先発医薬品から後発医薬品への切替えにより生じうる影響について検討するため薬物動態学的解析を行った。その結果、後発医薬品の血中移行性は皮膚透過性の影響を受けやすく、皮膚透過性が高まっている患者ではツロブテロールの副作用リスク増大や治療効果減弱をきたしうることが示唆された。

災害時における薬物治療の注意点-「薬が飲めない使えない」「生活・体調の変化」に対応した薬学的管理-.

澤田康文, 三木晶子, 堀里子, 佐藤宏樹, 大谷壽一, 大津史子.

日本病院薬剤師会雑誌 (日本病院薬剤師会) 47(9) 1101-1113 2011.09

Joint Work

Comparison of the inhibitory profiles of itraconazole and cimetidine in cytochrome P450 3A4 genetic variants.

Akiyoshi T, Saito T, Murase S, Mitsue Miyazaki M, Murayama N, Yamazaki H, Guengerich FP, Nakamura K, Yamamoto K, Ohtani H*.

Drug Metab Dispos (Drug Metabolism and Disposition) 39(4) ( 4 ) 724-8 - 728 2011.04

Research paper (scientific journal), Joint Work, Accepted, ISSN 00909556

CYP3A4, an important drug-metabolizing enzyme, is known to have genetic variants. We have previously reported that CYP3A4 variants such as CYP3A4.2, 7, 16, and 18 show different enzymatic kinetics from CYP3A4.1 (wild type). In this study, we quantitatively investigated the inhibition kinetics of two typical inhibitors, itraconazole (ITCZ) and cimetidine (CMD), on CYP3A4 variants and evaluated whether the genetic variation leads to interindividual differences in the extent of CYP3A4-mediated drug interactions. The inhibitory profiles of ITCZ and CMD on the metabolism of testosterone (TST) were analyzed by using recombinant CYP3A4 variants. The genetic variation of CYP3A4 significantly affected the inhibition profiles of the two inhibitors. In CYP3A4.7, the Ki value for ITCZ was 2.4-fold higher than that for the wild-type enzyme, whereas the Ki value for CMD was 0.64-fold lower. In CYP3A4.16, the Ki value for ITCZ was 0.54-fold lower than that for wild-type CYP3A4, whereas the Ki value for CMD was 3.2-fold higher. The influence of other genetic variations also differed between the two inhibitors. Docking simulations could explain the changes in the Ki values, based on the accessibility of TST and inhibitors to the heme moiety of the CYP3A4 molecule. In conclusion, the inhibitory effects of an inhibitor differ among CYP3A4 variants, suggesting that the genetic variation of CYP3A4 may contribute, at least in part, to interindividual differences in drug interactions mediated by CYP3A4 inhibition, and the pattern of the influences of genetic variation differs among inhibitors as well as substrates. Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics.

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下痢で薬の体内動態はどう変わる?.

大谷壽一.

薬局 (南山堂) 62(3) 378-383 2011.03

Single Work

未来先導型の研究と教育を目指して.

大谷壽一, 秋好健志.

薬剤学 (薬剤学) 70(4) 218-223 2010.07

Joint Work

代謝酵素が関係した相互作用パロキセチンとCYP2D6代謝薬剤.

大谷壽一.

薬局 (南山堂) 61(8) 2803-2807 2010.07

Single Work

併用禁忌・併用注意とは? どう決まる? どう判断する?.

大谷壽一, 佐藤宏樹, 澤田康文.

薬局 (南山堂) 61(8) 2767-2775 2010.07

Joint Work

類似名称による医薬品取り違え事故防止の試み.

玉木啓文, 堀里子, 佐藤宏樹, 三木晶子, 大谷壽一, 澤田康文.

日本病院薬剤師会雑誌 (日本病院薬剤師会) 46(6) 765-769 2010.06

Joint Work

Pharmacokinetic modeling of the dosing interval dependency of the interaction between itraconazole and triazolam.

Toi A, Ohtani H, Tsujimoto M, Sawada Y*.

Int J Clin Pharmacol Ther 48(6) 356-366 2010.06

Research paper (scientific journal), Joint Work, Accepted

Pharmacokinetic modeling of the dosing interval dependency for the interaction between itraconazole and triazolam

Toi A., Ohtani H., Tsujimoto M., Sawada Y.

International Journal of Clinical Pharmacology and Therapeutics (International Journal of Clinical Pharmacology and Therapeutics) 48 ( 6 ) 356 - 366 2010.06

ISSN 09461965

Objective: Itraconazole is a potent inhibitor of cytochrome P450 (CYP) 3A with an elimination half-life of more than 30 hours. Therefore, itraconazole may cause persistent CYP3A inhibition. Triazolam is primarily metabolized by CYP3A and its plasma concentration is increased remarkably by itraconazole. Although separating their dosages by 24 hours has been shown to reduce the interaction, an appropriate dosage interval remains to be determined. The aim of this study was to identify an appropriate dosage schedule to avoid their interaction. Materials and methods: We developed a pharmacokinetic model based on the assumption that both itraconazole and hydroxyitraconazole competitively and reversibly inhibit the first-pass metabolism and systemic elimination of triazolam. The developed model was simultaneously fitted to the plasma concentration profiles of triazolam, taken fromthe literature, by using the plasma concentration-time profiles of itraconazole and hydroxyitraconazole as input functions to estimate their in vivo Ki values. Subsequently, we simulated the plasma concentration profiles of triazolam administered after itraconazole therapy with various dosing intervals. Results: The model could explain and simulate the interaction between itraconazole-triazolam using a variety of dosage intervals between the administrations. Conclusions: The developed model may provide useful information with regard to the appropriate interval for triazolam administration during itraconazole therapy. ©2010 Dustri-Verlag Dr. K. Feistle.

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Saturable binding of finasteride to steroid 5-alpha-reductase as determinant of nonlinear pharmacokinetics.

Suzuki R, Satoh H, Ohtani H, Hori S, Sawada Y*.

Drug Metabol Pharmacokinet 25(2) 208-213 2010.04

Research paper (scientific journal), Joint Work, Accepted

Inhibitory effects of herbal extracts on breast cancer resistance protein (BCRP) and structure-inhibitory potency relationship of isoflavonoids.

Tamaki H, Satoh H, Hori S, Ohtani H, Sawada Y*.

Drug Metabol Pharmacokinet (Drug Metabolism and Pharmacokinetics) 25(2) ( 2 ) 170-179 - 179 2010.04

Research paper (scientific journal), Joint Work, Accepted, ISSN 13474367

The inhibition of intestinal breast cancer resistance protein (BCRP), which restricts the absorption of xenobiotics, may increase the systemic availability of its substrates. The aim of this study was to evaluate the inhibitory effects of herbal extracts and their constituents on BCRP-mediated transport. The inhibitory effects of 9 herbal extracts and 23 isoflavonoids, including soybean-derived isoflavones, on BCRP-mediated methotrexate (MTX) transport were evaluated using BCRP-expressing membrane vesicles. The structure-in-hibitory potency relationship was investigated by multiple factor analysis. Extracts of soybean, Gymnema sylvestre, black cohosh and passion flower and rutin strongly inhibited BCRP-mediated transport of MTX at 1 mg/ml, while inhibition by chlorella, milk thistle and Siberian ginseng extracts was weak. Among the 23 isoflavonoids examined, all of which inhibited BCRP-mediated transport, coumestrol showed the most potent inhibition (IC50=63 nM). The inhibitory potencies of 6 isoflavonoid glucosides were 10-to 100-fold lower than those of the corresponding aglycones. The addition of a 5-hydroxyl or 6-methoxyl moiety tended to potentiate the inhibition. The inhibitory potency of daidzein was decreased 100-fold by 7-glucuronidation, but was virtually unaffected by 4′-sulfation. Thus, some herbal and dietary supplements and isoflavonoids may increase the systemic availability of BCRP substrates when concomitantly given orally.

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和文誌の全文情報を閲覧・入手するためのサイトのご紹介.

大谷壽一.

医薬品情報学 (日本医薬品情報学会) 11(3) 192-195 2010.02

Single Work

Saturable binding of finasteride to steroid 5a-reductase as determinant of nonlinear pharmacokinetics

Suzuki R., Satoh H., Ohtani H., Hori S., Yasufumi S.

Drug Metabolism and Pharmacokinetics (Drug Metabolism and Pharmacokinetics) 25 ( 2 ) 208 - 213 2010

ISSN 13474367

Finasteride, a steroid 5a-reductase (5aR) inhibitor, is used to treat benign prostatic hyperplasia and androgenetic alopecia. We aimed to develop a pharmacokinetic/pharmacodynamic model to explain its nonlinear pharmacokinetics and describe the serum concentration profile of dihydrotestosterone (DHT) after finasteride administration. We developed a pharmacokinetic model incorporating a compartment that represents the binding of finasteride to 5aR. We fitted this model to the time-concentration profiles of finasteride after repeated administration of finasteride 0.2 and 1 mg/day. We constructed a pharmacodynamic model considering the inhibition of 5aR type I and type II (5aR1 and 5aR2). This model was fitted to the time profiles of serum DHT. The developed pharmacokinetic model well described nonlinear increase in AUC after repeated administration of finasteride. The association and dissociation rate constants were estimated to be 0.0293/nmol/hr and 0.0185/hr, respectively. Pharmacodynamic model analysis suggested that the 5aR1 inhibition is dose-dependent in the dose range from 0.2 to 100 mg, while the 5aR2 inhibition is almost saturated in the same dose range. Finasteride's saturable binding to 5aR2 is the likely cause of its nonlinear pharmacokinetics. The developed pharmacokinetic/pharmacodynamic model should allow prediction of plasma concentration profiles of finasteride and DHT.

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医薬品情報学研究のあり方-ワークショップにおけるKJ法に基づく問題抽出と解析-.

山田安彦, 澤田康文*, 山本康次郎, 飯久保尚, 大谷壽一, 上村直樹, 安部好弘, 上原恵子, 太田隆文, 折井孝男, 岸本紀子, 齋藤充生, 武立啓子, 樽野弘之, 近澤洋平, 仲佐啓詳, 橋口正行, 堀里子, 山元俊憲.

医薬品情報学 ((一社)日本医薬品情報学会) 11(2) ( 2 ) 76-87 - 87 2009.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 1345-1464

日本医薬品情報学会(JASDI)は医薬品情報学のあり方を提言することを目的に、ビジョン委員会を発足させた。当該委員会では医薬品情報学の教育が抱える問題点を、KJ法を用いて抽出、明確化することを目的に、2008年7月の第11回JASDI学会においてワークショップを開催した。抽出された大きな問題点は「医薬品情報の範囲が広すぎること」と「医薬品情報の定義とシステムが不明確なこと」であった。関連する問題点は歴史の浅さと独自性の欠如であった。また、研究の方法論が十分に確立していないこと、教育のシステム化ができていないことも指摘された。本ワークショップにより、医薬品情報学の抱える「本学問の定義づけ、体系化ができていない」という問題点が明確化すると共に、参加者に対しても有意な意識変化をもたらしたことが明らかになった。

患者の健康食品使用に関する薬剤師の行動実態調査.

朝比奈泰子, 堀里子, 大谷壽一, 澤田康文.

医療薬学 ((一社)日本医療薬学会) 35(10) ( 10 ) 685-692 - 692 2009.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 1346-342X

臨床現場の薬剤師が患者の健康食品使用に対してどのように関わっているのか、また、健康食品情報の収集状況、被害情報の収集・アウトプットといった行動の現状を明らかにすることを目的として、著者らが2000年より構築・運営しているインターネットによる全国薬剤師間情報交換・研修システムi-PHISSを介してアンケートを行った。323名から回答が得られ、内訳は薬局薬剤師219名、病診薬剤師104名であった。処方箋受付時に患者の健康食品使用の有無を確認するか?という薬局薬剤師への問いに対して、「必ず確認する」と回答した人が29%、「必要に応じて確認する」が58%、「患者からの申し出がない限り確認しない」が12%であった。入院患者に健康食品使用の有無を確認するか?という病診薬剤師への問いに対して、「必ず確認する」と回答した人が44%、「必要に応じて確認する」が32%、「患者からの申し出がない限り確認しない」が10%であった。

医療従事者を対象として定期的に健康食品情報を提供するインターネット研修システムの構築とその評価.

朝比奈泰子,堀里子,大谷壽一,澤田康文*.

薬学雑誌 ((公社)日本薬学会) 129(6) ( 6 ) 773-780 - 780 2009.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 0031-6903

著者らは、2000年より薬剤師間情報交換・研修システム「Internet-based Pharmacist's Information-Sharing System(i-PHISS)」、2005年より医師間情報交換・研修システム「Internet-based Medical Doctor's Information-Sharing System(i-MEDISS)」を構築・運用してきた。これらシステムは、医療従事者の知識・技能・態度の研鑽、医療ミスの低減を目的として、インターネットを介して医療従事者から臨床現場で起きた医薬品に関するアクシデント・インシデント事例を収集し、それら事例にエビデンスに基づく検討・解説を加えて再度配信する登録制のシステムである。今回、両システムを活用して、医薬品のみならず健康食品に関しても医療従事者のニーズに沿った情報コンテンツを作成し、定期的な提供を行うようにした。このサービスに対するi-PHISS・i-MEDISS登録者の評価をウェブアンケートによって調査した結果、概ね好評であり、健康食品に対する医療従事者の関心を喚起できていたことが確認された。

Quantitative comparison of the convulsive activity of combinations of twelve fluoroquinolones with five nonsteroidal antiinflammatory agents.

Kim J,Ohtani H, Tsujimoto M, Sawada Y.

Drug Metabol. Pharmacokinet (Drug Metabolism and Pharmacokinetics) 24(6) ( 2 ) 167-174 - 174 2009.05

Research paper (scientific journal), Joint Work, Accepted, ISSN 13474367

Concomitant administration of certain fluoroquinolone antimicrobials and nonsteroidal antiinflammatory agents (NSAIDs) induces serious convulsion in humans. There are differences in convulsive activity among fluoroquinolones and in the potentiation of fluoroquinolone-induced convulsion among NSAIDs, but a comprehensive, quantitative comparison has not been carried out. This study evaluates the inhibitory effects of twelve fluoroquinolones (ciprofloxacin, enoxacin, fleroxacin, gatifloxacin, levofloxacin, lomefloxacin, norfloxacin, ofloxacin, pazufloxacin, prulifloxacin, sparfloxacin, and tosufloxacin) alone or in the presence of an NSAID (4-biphenylacetic acid, diclofenac sodium, loxoprofen, lornoxicam or zaltoprofen) on the GABAA receptor binding of [3H]muscimol in an in vitro study using mice synaptic plasma membrane. The rank order of inhibitory effects of the fluoroquinolones was prulifloxacin≈norfloxacin> ciprofloxacin≥enoxacin>gatifloxacin≥ ofloxacin≈tosufloxacin≈lomefloxacin> levofloxacin≥sparfloxacin≥ pazufloxacin≈fleroxacin. 4-Biphenylacetic acid most potently enhanced the inhibitory effects of the fluoroquinolones, while zaltoprofen, loxoprofen, lornoxicam and diclofenac had essentially no effect. The clinical risk of convulsion for each combination was estimated using a pharmacodynamic model based on receptor occupancy using the in vitro data set obtained and pharmacokinetic parameters in humans collected from the literature. The combinations of 4-biphenylacetic acid with prulifloxacin and enoxacin were concluded to be the most hazardous.

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Transplacental pharmacokinetics of diclofenac in perfused human placenta.

Shintaku K, Hori S, Tsujimoto M, Nagata H, Satoh S, Tsukimori K, Nakano H, Fujii T, Taketani Y, Ohtani H, Sawada Y.

Drug Metab Dispos (Drug metabolism and disposition: the biological fate of chemicals) 37 ( 5 ) 962-968 - 968 2009.05

Research paper (scientific journal), Joint Work, Accepted, ISSN 0090-9556

The aims of this study were to evaluate the transplacental transfer properties of diclofenac and to determine the effect of L-lactic acid on the transplacental transfer of diclofenac. The maternal and fetal vessels of human placenta were perfused in a single-pass mode with a solution containing diclofenac and antipyrine. The transplacental pharmacokinetic model was fitted to the time profiles of the drug concentrations in the effluent and placenta to obtain transplacental pharmacokinetic parameters. In addition, chloride ion in the perfusate was partially replaced with L-lactic acid to see the change in the transplacental transfer properties of diclofenac. The TPT(ss) value (ratio of the rate of amount transferred across the placenta to that infused in the steady state) of diclofenac was 2.22%, which was approximately one-third that of antipyrine and was significantly reduced in the presence of L-lactic acid. The transplacental pharmacokinetic model could adequately explain the transplacental transfer of diclofenac with influx clearances from maternal and fetal perfusates to placental tissue of 0.276 and 0.0345 ml/min/g cotyledon and efflux rate constants from placental tissue to maternal and fetal perfusates of 0.406 and 0.0337 min(-1), respectively. By taking into account protein binding, the placental tissue/plasma concentration ratio in humans for diclofenac was estimated to be 0.108 ml/g of cotyledon and was smaller than that of antipyrine. In conclusion, human placental perfusion and transplacental pharmacokinetic modeling allowed us to determine the transplacental transfer properties of diclofenac quantitatively. Diclofenac may share transplacental transfer system(s) with L-lactic acid.

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Co-administration of proton pump inhibitors delays elimination of plasma methotrexate in high-dose methotrexate therapy.

Suzuki K, Doki K, Homma M, Tamaki H, Hori S, Ohtani H, Sawada Y, Kohda Y.

Br. J. Clin. Pharmacol (British Journal of Clinical Pharmacology) 67(1) ( 1 ) 44-49 - 49 2009.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 03065251

AIM: To assess whether or not co-administration of proton pump inhibitors (PPIs) is a risk factor for delayed elimination of plasma methotrexate (MTX) in high-dose MTX (HDMTX) therapy for malignant diseases. METHODS: To assess the effects of PPI co-administration on elimination of plasma MTX, we examined plasma MTX concentration data on 171 cycles of HDMTX therapy performed in 74 patients. We performed multiple logistic regression analysis to evaluate PPI co-administration as a risk factor. Inhibitory potencies of omeprazole, lansoprazole, rabeprazole and pantoprazole on MTX transport via breast cancer resistance protein (BCRP, ABCG2) were also investigated in an in vitro study using membrane vesicles expressing human BCRP. RESULTS: We identified co-administration of PPIs as a risk factor for delayed elimination (odds ratio 2.65, 95% confidence interval 1.03, 6.82) as well as renal and liver dysfunction. All four PPIs inhibited BCRP-mediated transport of MTX, with half-maximal inhibitory concentrations of 5.5-17.6 μM - considerably higher than the unbound plasma concentrations of the PPIs. CONCLUSIONS: Our results support previous findings suggesting that PPI co-administration is associated with delayed elimination of plasma MTX in patients with HDMTX therapy. This drug interaction, however, cannot be explained solely by the inhibitory effects of PPIs on BCRP-mediated MTX transport. © 2008 The Authors.

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Effect of smoking and CYP2D6 polymorphisms on the extent of fluvoxamine-alprazolam interaction in patients with psychosomatic disease.

Sugahara H, Maebara C, Ohtani H, Handa M, Ando K,Mine K,Kubo C, Ieiri I, Sawada Y.

Eur J Clin Pharmacol (European Journal of Clinical Pharmacology) 65 ( 7 ) 699-704 - 704 2009.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 00316970

Purpose: Fluvoxamine (FVX) is metabolized by cytochrome P450 (CYP) 2D6 and CYP1A2 and inhibits CYP3A4. The aim of this study was to investigate the factors responsible for interindividual variability in the extent of interaction between FVX and alprazolam (ALP). Methods: Blood samples were taken from 49 depressive patients to determine plasma concentration of FVX, ALP or both. Twenty-four samples were taken during the FVX-alone period, 21 samples during the ALP-alone period and 30 samples during the FVX-ALP period. Subjects were also genotyped for CYP2D6. Results: The concentration-to-dose (C/D) ratio of ALP during the FVX-treatment period was significantly higher than that during the ALP-alone period. The CYP2D6 genotype affected neither the C/D ratios of FVX nor the extent of interaction. The mean C/D ratio of FVX in smokers was reduced by more than 30% in comparison with that in non-smokers. The mean C/D ratio of ALP in non-smokers was increased by FVX, while that in smokers was unchanged. Conclusions: The extent of interaction between FVX and ALP may be affected by smoking, which alters the C/D ratio of FVX. Therefore, when FVX and ALP are concomitantly administered, it should be noted that non-smokers may exhibit greater drug interaction than smokers. © 2009 Springer-Verlag.

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Inhibitory effects of herbal extracts on the activity of human sulfotransferase isoform SULT1A3.

Nagai M, Fukamachi T, Tsujimoto M, Ogura K, Hiratsuka A, Ohtani H,Hori S, Sawada Y.

Biol. Pharm. Bull 32(1) 105-109 2009.01

Research paper (scientific journal), Joint Work, Accepted

Inhibitory effects of herbal extracts on the activity of human sulfotransferase isoform sulfotransferase 1A3 (SULT1A3)

Nagai M., Fukamachi T., Tsujimoto M., Ogura K., Hiratsuka A., Ohtani H., Hori S., Sawada Y.

Biological and Pharmaceutical Bulletin (Biological and Pharmaceutical Bulletin) 32 ( 1 ) 105 - 109 2009.01

ISSN 09186158

Sulfotransferase 1A3 (SULT1A3) is a phase II detoxifying enzyme of xenobiotics predominantly expressed in the intestinal epithelium. Recent increase in the use of herbal extracts as dietary supplements may lead to an increase in the possibility of dietary supplement-drug interactions. The purpose of the present study was to investigate the effects of 18 herbal extracts on SULT1A3 activity and the possibility of interaction between medicinal drugs and herbal extracts. We examined the inhibitory potencies of 18 herbal extracts on the sulfation of dopamine, a typical substrate of SULT1A3, and ritodrine, a β 2 stimulant, by human recombinant SULT1A3. The sulfation of dopamine was inhibited by extracts of banaba, green tea, Rafuma, grape seed, peanut seed coat, gingko biloba leaf, St. John's wort, gymnema and milkthistle. The IC 50 values of these herbal extracts were lower than the putative gastrointestinal concentration when the recommended dose was ingested. On the other hand, chlorella extract and rutin showed no inhibitory effects and wheat, mulberry and siberian ginseng had IC 50 values exceedingly higher than the putative gastrointestinal concentration. The inhibitory profiles of herbal extracts for the sulfation of ritodrine were comparable to those for the sulfation of dopamine. In conclusion, the extracts of herbs such as banaba and green tea potently inhibited SULT1A3 activity. These extracts may increase the bioavailability of drugs whose bioavailabilities were limited by the function of SULT1A3 on the intestinal epithelium. © 2009 Pharmaceutical Society of Japan.

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The first case of phenytoin intoxication associated with the concomitant use of phenytoin and TS-1, a combination preparation of tegafur, gimeracil, and oteracil potassium.

Tsuda A, Fujiyama J, Miki A, Hori S, Ohtani H, Sawada Y*.

Cancer Chemotherapy and Pharmacology (Cancer Chemotherapy and Pharmacology) 62(3) ( 3 ) 427-432 - 432 2008.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 03445704

Purpose: We reported the first case of phenytoin intoxication due to the concomitant use of phenytoin and TS-1, together with a review of the literature regarding the occurrence of phenytoin intoxication due to the concomitant use of phenytoin and fluoropyrimidine antitumor drugs such as fluorouracil (5-FU) and tegafur (FT). Methods: We showed the clinical course of our patient. Reports of phenytoin intoxication due to the concomitant use of phenytoin and fluoropyrimidine antitumor drugs in the English and Japanese language literature up to 2007 were identified by searching Medline and ICHUSHI Web (Japana Centra Revuo Medicina). Results: A patient taking phenytoin and TS-1, a combination preparation of tegafur, gimeracil, and oteracil potassium, experienced lightheadedness and repeated falls associated with an increase in serum phenytoin concentration (32.8 μg/ml) at 1 month after the start of TS-1 treatment. The time lag between initiation of combined treatment and onset of adverse symptoms suggests the presence of an indirect mechanism, rather than direct inhibition of drug-metabolizing enzymes by drugs in TS-1 or their active metabolites. Conclusions: Plasma phenytoin concentration should be closely monitored in patients receiving TS-1 and phenytoin concomitantly. © 2007 Springer-Verlag.

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Effects of uremic serum and uremic toxins on hepatic uptake of digoxin.

Tsujimoto M, Kinoshita Y, Hirata S, Otagiri M, Ohtani H, Sawada Y.

Ther. Drug Monit (Therapeutic Drug Monitoring) 30(5) ( 5 ) 576-582 - 582 2008.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 01634356

Not only the renal clearance but also the hepatic clearance of drugs varies with the progression of renal failure. The aim of this study was to investigate the effects of human uremic serum and various uremic toxins on the hepatic uptake of digoxin (DX), a drug mainly excreted into bile in patients with severe renal failure, using isolated rat and human hepatocytes as model systems. Uremic serum inhibited the uptake of DX into rat hepatocytes in a concentration-dependent manner, whereas normal serum did not affect the uptake. In addition, 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), hippuric acid, indole-3-acetic acid, indoxyl sulfate, and p-cresol (PC) concentration dependently inhibited the uptake. CMPF and PC at the concentration of 400 μΜ, which is within the plasma concentration range attained in patients with renal failure, inhibited the uptake of DX into rat hepatocytes by 27% and 23%, respectively. In human hepatocytes, 10% uremic serum, 400 μΜ CMPF, and 400 μΜ PC inhibited the uptake of DX by 23.3%, 23.4%, and 28.2%, respectively. In conclusion, our results suggest that hepatic uptake of DX is likely to be inhibited by uremic toxins, such as CMPF and PC, present in the serum of patients with renal failure. Copyright © 2008 by Lippincott Williams & Wilkins.

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青汁をはじめとする健康食品の使用実態・意識調査.

朝比奈泰子, 本間秀彰, 堀里子, 大谷壽一, 三木晶子, 後藤輝明, 河野弘之, 澤田康文.

医療薬学 ((一社)日本医療薬学会) 34(7) ( 7 ) 644-650 - 650 2008.07

Research paper (scientific journal), Joint Work, Accepted, ISSN 1346-342X

ドラッグストアを訪れた消費者を対象に、青汁を飲む動機、青汁の安全性と有効性についての認識、サプリメント一般に関する情報の必要性など青汁の使用実態をアンケート調査した。2006年2〜3月に北海道、東北、関東地方のツルハの調剤併設ドラッグストア68店を訪れた患者、消費者563名を調査対象とした。青汁服用者は65歳以上の高齢者、降圧薬、抗アレルギー薬、糖尿病治療薬の長期間服用者で有意に多かった。33.2%は効果があると考えていたが、55%はわからないと答えた。青汁服用による体調不良は2.4%で起った。その他、毎日服用(55.5%)、注意事項不読(27%)などであった。青汁服用は長期医薬品服用の高齢者に多いことが判明した。青汁服用の効果と副作用についての証拠を集め、消費者に注意事項が確実に伝わる方法を検討する必要がある。

Influence of SLCO1B3 gene polymorphism on the pharmacokinetics of digoxin in terminal renal failure.

Tsujimoto M, Dan Y, Hirata S, Ohtani H, Sawada Y.

Drug Metabol. Pharmacokinet (Drug Metabolism and Pharmacokinetics) 23(6) ( 6 ) 406-411 - 411 2008.05

Research paper (scientific journal), Joint Work, Accepted, ISSN 13474367

Digoxin (DX) is mainly excreted unchanged in the urine. In patients undergoing hemodialysis (HD patients), the relative contribution of hepatic elimination is increased. DX is a substrate of OATP1B3 (SLCO1B3), expressed on the sinusoidal membranes of hepatocytes in humans. Therefore, we investigated the relationship between SLCO1B3 gene polymorphisms and the value of trough concentration-to-dose ratio (C/D ratio) of DX in HD patients. We investigated two deletion polymorphisms in complete linkage disequilibrium (-28 to -11 and -7 to -4) and two SNPs in complete linkage disequilibrium (T334G and G699A). Blood was sampled 62-72 hours after the oral administration of DX. The C/D ratio of DX was lower in patients with the deletion allele than in those homozygous for the insertion allele, and was lower in patients with the 334T/669G allele than in those homozygous for the 334G/699A allele, although the differences were not statistically significant. The C/D ratio of DX was significantly higher in patients with homozygous for the insert-variant allele (median: 121.8 (ng/mL)/(mg/week/kg), range: 92.5-259.4 (ng/mL)/(mg/week/kg) than in others (median: 93.4 (ng/mL)/(mg/ week/kg), range: 66.5-154.3 (ng/mL)/(mg/week/kg)). In conclusion, the insert-variant allele of the OATP1B3 gene may increase the C/D ratio of DX in HD patients.

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患者を対象としたケトプロフェンテープの使用感に関する製剤間比較調査.

斉田翌美, 井上綾子, 石橋久, 冨永宏治, 堀里子, 三木晶子, 大谷壽一, 小野信昭, 澤田康文.

薬学雑誌 ((公社)日本薬学会) 128(5) ( 5 ) 795-803 - 803 2008.05

Research paper (scientific journal), Joint Work, Accepted, ISSN 0031-6903

46歳女性にKPテープ先発品Aを1日1回痛みに応じて、腰部と膝関節に貼付していたが、後発品Bに変更した後、使用感の相違が生じた。そこでA使用者39名(男6名、女33名、20〜86歳)とB使用者27名(男7名、女20名、39〜85歳)を対象に、テープ剤、外袋、ライナーについて調べ、テープ剤の評価を行い、貼付後の患部の状態についても調べた。先発品Aと後発品Bには使用感に差があり、先発品Aは後発品Bに比較し高く評価される傾向が認められた。先発品A使用経験を有する患者は使用経験がない患者に比べ、後発品Bに対する評価が低い傾向がみられた。貼付剤の使用感に関する比較試験は採用薬の選定や製剤切り替え時の服薬指導に有用である。

Genetic polymorphisms in the 5-hydroxytryptamine type 3B receptor gene and paroxetine-induced nausea.

Tanaka M, Kobayashi D, Murakami Y, Ozaki N, Suzuki T, Iwata N, Haraguchi K, Ieiri I, Kinukawa N, Hosoi M, Ohtani H, Sawada Y, Mine K*.

International Journal of Neuropsychopharmacology (International Journal of Neuropsychopharmacology) 11(2) ( 2 ) 261-267 - 267 2008.03

Research paper (scientific journal), Joint Work, Accepted, ISSN 14611457

Selective serotonin reuptake inhibitor (SSRI)-induced nausea can be severe enough to lead to early treatment discontinuation. However, it is currently not possible to predict the occurrence of nausea before the initiation of SSRI treatment. In this study, we investigated the effect of genetic polymorphisms in the 5-hydroxytryptamine type 2A, 3A, and 3B (5-HT3B) receptors, 5-HT transporter, and CYP2D6 genes on the incidence of paroxetine-induced nausea. A consecutive series of 72 Japanese patients with depressive or anxiety disorders were treated with paroxetine. Paroxetine-induced nausea was assessed by a pharmacist and was observed in 29.2% of the patients. A significant (nominal p=0.00286) association was found between the incidence of nausea and the -100_-102AAG insertion/deletion polymorphism of the 5-HT3B receptor gene. No significant associations were observed between the other genetic polymorphisms and the incidence of nausea. The -100_-102AAG deletion variant of the 5-HT3B receptor gene may a.ect paroxetine-induced nausea. © 2007 Collegium Internationale Neuropsychopharmacologicum.

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クラリスロマイシンドライシロップと各種カルボシステイン製剤併用時の苦味強度における先発医薬品と後発医薬品間の違い.

松尾律子, 田中祥子, 加納美知子, 磯野喜美子, 田中泰羽, 田浦智子, 浅田由貴, 赤嶺有希子, 沢井一, 木下正和, 須藤智美, 久野木良子, 三木晶子, 堀里子, 佐藤宏樹, 大谷壽一, 澤田康文.

薬学雑誌 ((公社)日本薬学会) 128(3) ( 3 ) 479-485 - 485 2008.03

Research paper (scientific journal), Joint Work, Accepted, ISSN 0031-6903

クラリスロマイシンドライシロップ(CAM-DS)と、カルボシステイン(CC)製剤であるムコダインドライシロップ(MDS)及びムコダイン細粒(MGr)を同時処方した場合の苦味発現の程度について検討した。健康成人男性5名を対象に官能実験を行い、苦味強度を5段階評価した。先発品CAM-DSや、MDS,MGrはそれぞれ単独では苦味強度は低いが、CAM-DSをMDS,MGr又はMGr1(MGr後発品)と混合すると苦味強度が有意に増加した。先発品を含むCAM-DSの9製剤をMDSと混合したところ、後発品CDS7において苦味増加度が他剤と比較して有意に低かった。後発品を含むCCシロップは、先発品CAM-DSと混合した場合、CAM-DS+MDSより苦味強度が有意に低かった。

Bitterness of the mixture of clarithromycin dry syrup and carbocisteine preparation-difference between branded and generic drugs

Matsuo R., Tanaka S., Kanou M., Isono K., Tanaka Y., Taura T., Asada Y., Akamine Y., Sawai H., Kinosita M., Sudou T., Kunoki Y., Miki A., Hori S., Satoh H., Ohtani H., Sawada Y.

Yakugaku Zasshi (Yakugaku Zasshi) 128 ( 3 ) 479 - 485 2008.03

ISSN 00316903

The purpose of this study was to assess the bitterness intensity and pH of the solutions of clarithromycin dry syrup (CAM-DS), carbocisteine preparation (CC), and the concomitant use of both drugs. We conducted 6 types of human gustatory sensation tests with 6 healthy male volunteers. As a result, there was almost no difference in the bitterness intensity of CAM-DS between the branded (the latest and former preparations) and the generic formulations. The bitterness intensity of CAM-DS (the latest and former preparations of the branded as well as the generic formulations) was almost equally enhanced by mixing it with either the branded CC-DS or the branded and the generic carbocisteine granule (CC-Gr). On this occasion, the enhancing the bitterness of the branded CAM-DS (latest and former preparation) was nearly avoided safely by dosage form's changing CC-DS or CC-Gr to the branded CC-Sy. However, unlike the branded CC-Sy, some generic CC-Sy failed to suppress the bitterness. Furthermore, it was proven that some generic CAM-DS were shown to exhibit bitterness when mixed with even branded CC-Sy. In conclusion, it should be noted that the extent of bitterness of the mixture of CAM-DS and CC highly varies among the generic formulations. © 2008 The Pharmaceutical Society of Japan.

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Inhibitory effects of various beverages on human recombinant sulfotransferase isoforms SULT1A1 and SULT1A3.

Nishimuta H, Ohtani H, Tsujimoto M, Ogura K, Hiratsuka A, Sawada Y*.

Biopharmaceutics and Drug Disposition (Biopharmaceutics and Drug Disposition) 28(9) ( 9 ) 491-500 - 500 2007.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 01422782

Sulfotransferase (SULT) 1A1 and SULT1A3 play important roles in the presystemic inactivation of β2 agonists in the liver and intestine, respectively. The study aimed to investigate the inhibitory effects of grapefruit juice, orange juice, green tea, black tea and oolong tea and their constituents on the activities of SULT1A1 and SULT1A3. The activities of both SULT1A1 and SULT1A3 were significantly inhibited by all the beverages investigated at a concentration of 10%. The beverage constituents were tested in concentration ranges considered to be physiologically relevant. The grapefruit constituent, quercetin, completely inhibited SULT1A1, while quercetin and naringin both partially inhibited SULT1A3. The orange constituents, tangeretin and nobiletin, also completely inhibited SULT1A1. The tea constituents, (-)-epicatechin gallate and (-)-epigallocatechin gallate, both almost completely inhibited SULT1A1 and SULT1A3. Moreover, the theaflavin and thearubigin fractions of black tea both completely inhibited SULT1A1 and strongly inhibited SULT1A3. The inhibitory action of green tea on SULT1A3 was competitive, while that of black tea and oolong tea was mixed competitive/non-competitive. Mechanism-based inhibition was not observed with any beverage. In conclusion, various beverages, especially teas, inhibit the function of SULT1A3, and therefore may have the potential to increase the bioavailability of orally administered substrates of SULT1A3, such as β2 agonists. Copyright © 2007 John Wiley & Sons, Ltd.

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Relationship between MDR-1 polymorphism and brain penetration of fexofenadine, an antihistamine, evaluated by PET with [11C]doxepin

Tashiro M., Tsujimoto M., Kato M., Ohtani H., Itoh M., Sawada Y., Yanai K.

Journal of Cerebral Blood Flow and Metabolism (Journal of Cerebral Blood Flow and Metabolism) 27 ( SUPPL. 1 ) BP20 - 07 2007.11

ISSN 0271678X

Background and aims: Histamine H1 receptor (H1R) antagonists, or antihistamines, mainly act on the peripheral tissues but can induce sedation. This undesirable central side effect is caused by blockade of nerve transmission in the histaminergic neuron system. Variation in sedative properties of antihistamines is due to difference in their blood-brain barrier (BBB) permeability, partly defined by activity of P-glycoprotein (P-gp), an efflux pump located in the membrane of endothelial cells in brain capillaries. The aim of the present study is to evaluate the effects of single nucleotide polymorphisms (SNP) of the P-gp encoding "multi-drug resistance gene (MDR)-1" on BBB permeability of a non-sedative antihistamine, fexofenadine, that is a substrate of P-gp, using positron emission tomography (PET) with [11C]doxepin. Methods: Healthy young male volunteers (n=39, ranging 19-36 y.o.) were recruited and examined for genotyping of the common SNP in exon 26 (C3435T). Twenty-two out of the 39 subjects were studied by PET with [11C]doxepin following oral administration of placebo or fexofenadine 120 mg, in a single blind cross-over design. PET scan started 90 min following administration of each drug and the dynamic data, obtained taking 90 min, were analyzed based on Logan reference method to yield binding potential in various cortical structures. Based on the biding potential data of each subject in two drug conditions, histamine H1 receptor occupancy (H1RO) due to fexofenadine was calculated for each subject and the individual H1RO values were compared between wild-type (CC: n=6), heterozygous (CT: n=13) and homozygous (TT: n=3) subgroups. Results: Overall mean H1RO due to fexofenadine in the 22 subjects was calculated as -5%. The mean H1ROs of the 3 subgroups, CC, CT and TT, were -13.4, -3.7 and -1.4%, respectively, although the difference was not significant. Conclusions: The reason that H1RO of fexofenadine was calculated as lower than zero is not known. The PET results might suggest the presence of slight decrease in efflux function of P-glycoprotein in BBB among holders of C3435T mutation in comparison to wild-type in human. Further investigation is needed to draw a definitive conclusion with larger sample size, including studies on other mutations and other influx and efflux transporters. Functional and molecular imaging will be a strong tool for establishment of "individualized medicine".

Effects of various methoxyflavones on vincristine uptake and multidrug resistance to vincristine in P-gp-overexpressing K562/ADM cells.

Ohtani H, Ikegawa T, Honda Y, Kohyama N, Morimoto S, Shoyama Y, Juichi M, Naito M, Tsuruo T, Sawada Y*.

Pharmaceutical Research (Pharmaceutical Research) 24(10) ( 10 ) 1936-1943 - 1943 2007.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 07248741

Purpose. Some methoxyflavones (MFs) are known to inhibit the function of P-glycoprotein. The aim of this study is to characterize the reversal of multidrug resistance (MDR) by MFs. Methods. The effects of 19 MFs, including 3,5,6,7,8,3′,4′-heptamethoxyflavone, nobiletin, and tangeretin, and flavone on the uptake of [3H]vincristine into an adriamycin-resistant variant of human chronic myelogenous leukemia (K562/ADM) cells were investigated. Potentiation of vincristine-induced growth inhibition by these MFs was also tested in K562/ADM cells by means of WST-1 [2-(4-iodophenyl)-3-(4- nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium] assay. Results. All MFs (20 μM) tested increased the uptake of [3H]vincristine. 3,5,6,7,8,3′,4′-heptamethoxyflavone, nobiletin, tangeretin, quercetagetin and quercetin pentamethylether showed especially potent effects. The increase in the uptake of [3H]vincristine was proportional to the number of methoxyl moieties. While substitution with a methoxyl moiety at the C3 position was the most influential, methoxyl substitution at both the C3′ and C5′ positions resulted in a decrease in the potentiation of uptake. Furthermore, there was a significant correlation between the potencies for increasing [3H]vincristine uptake and for growth inhibition assessed by WST-1 assay. Conclusions. MFs increased the uptake of [ 3H]vincristine into MDR cells and exhibited MDR-reversing effects. Their potencies were influenced by the number and positions of the methoxyl moieties. © 2007 Springer Science+Business Media, LLC.

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Possible case of potentiation of the antiplatelet effect of cilostazol by grapefruit juice.

Taniguchi K, Ohtani H, Ikemoto T, Miki A, Hori S, Sawada Y*.

Journal of Clinical Pharmacy and Therapeutics (Journal of Clinical Pharmacy and Therapeutics) 32(5) ( 5 ) 457-459 - 459 2007.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 02694727

We present a case of purpura associated with concomitant ingestion of cilostazol, aspirin and grapefruit juice. A 79-year-old man with atherosclerosis obliterans, taking cilostazol and aspirin, complained of purpura. Interview by a pharmacist revealed that he had been taking grapefruit juice for a month. His purpura disappeared upon cessation of grapefruit juice, although his medication was not altered. The most probable cause of his purpura is an increase in the blood level of cilostazol because of the inhibition of cilostazol metabolism by components of grapefruit juice. Aspirin may possibly have potentiated the risk of purpura. Grapefruit juice should be avoided in patients taking cilostazol, especially in patients being concomitantly treated with other anticoagulants. © 2007 The Authors.

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後発医薬品の使用に伴い生じたインシデント・アクシデント事例の実態とその解析.

堀里子, 寺門千佳子, 石河利恒, 大和田邦明, 宇野幹子, 三木晶子, 大谷壽一, 天野武城, 澤田康文*.

医薬品情報学 ((一社)日本医薬品情報学会) 9(3) ( 3 ) 205-209 - 209 2007.09

Research paper (scientific journal), Joint Work, Accepted, ISSN 1345-1464

東京23区及び多摩地区の医療機関、保険調剤薬局に後発医薬品に関するアンケート用紙を配布し、臨床において後発医薬品が関係して生じたトラブルの事例を収集し、その要因を分析した。アンケートの総回答数は1148件(回収率64.9%)であった。後発医薬品が関係したインシデント・アクシデント事例として87例を収集した。医薬品の取り違えは49件と最も多く、その多くは薬名が類似しているものであった。次いで、先発医薬品と後発医薬品の適応症の違いが11件、使用感・服用感の違いが9件などであった。後発医薬品への切り替えに伴う効果の増強・減弱や有害事象の発生に関する訴えが5件収集されたが、これらの事象と後発医薬品への切り替えとの因果関係は不明である。

健康食品に関する使用実態調査研究の統合により見いだされた諸問題解決のための提案

朝比奈泰子, 堀里子, 大谷壽一, 佐倉統, 澤田康文

医薬品情報学 ((一社)日本医薬品情報学会) 9 ( 2 ) 150 - 157 2007.08

ISSN 1345-1464

国民の健康食品への意識、使用動向を明らかにし、健康食品の安心・安全を確保するための方法を提案することを目的として、健康食品の使用実態や消費者・医療従事者の健康食品に関する意識を国内で調査・解析した過去の報告を収集し、統合を行った。十分な回答者数があり(N=300以上)、調査対象及び調査方法が明らかな9件のアンケート調査を選定し、使用目的、医療従事者と消費者との情報共有、情報の入手先と使用のきっかけ、健康食品の購入と入手先、健康被害の経験に関するデータを抽出し、解析した。その結果、健康食品に関して、健康被害をはじめとする多くの情報が見落とされ、また消費者がテレビやインターネット等で発信される不確かな情報を参考に健康食品を使用している可能性があるという現状が明らかになった。これらの結果を踏まえ、健康食品の安心・安全を確保するための全国ネットワークを提案した。

Effects of dosing interval on the pharmacokinetic interaction between oral small spherical activated charcoal and amlodipine in humans.

Tanaka C, Ohtani H, Tsujimoto M, Ohdo S, Taniguchi M, Mizooku Y, Saitoh Y, Kimura M, Uchimaru H, Irie S, Sawada Y*.

Journal of Clinical Pharmacology (Journal of Clinical Pharmacology) 47(7) ( 7 ) 904-908 - 908 2007.07

Research paper (scientific journal), Joint Work, Accepted, ISSN 00912700

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Piloerection induced by replacing fluvoxamine with milnacipran.

Hori S, Matsuo N, Yamamoto A, Hazui T, Yagi H, Nakano M, Suzuki Y, Miki A, Ohtani H, Sawada Y*.

British Journal of Clinical Pharmacology (British Journal of Clinical Pharmacology) 63(6) ( 6 ) 665-671 - 671 2007.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 03065251

Aims: To present a case of piloerection after replacing fluvoxamine maleate with milnacipran hydrochloride, and to analyse this effect based on receptor occupancy theory. Methods: A 40-year-old female with a 3-year history of panic disorder was prescribed fluvoxamine 50 mg day-1 in addition to clorazepate dipotassium and sulpiride. Depression was not improved and she complained of fatigue, lack of energy and drowsiness. These symptoms worsened within a few days of an increase in the dose of fluvoxamine to 50 mg twice daily. Since an interaction between fluvoxamine and tizanidine, prescribed by another clinic, was suspected, fluvoxamine was replaced with milnacipran 50 mg day-1. Although her drowsiness improved, she complained of piloerection throughout her body. This symptom gradually abated within a week and when the dosage of milnacipran was increased to 100 mg day-1 at 2 months, no further piloerection occurred. We calculated the changes in α1-adrenoceptor occupancy by endogenous norepinephrine during treatment with the usual doses of milnacipran, fluvoxamine and imipramine by using pharmacokinetic and pharmacodynamic parameters obtained from the literature. Results: The ratios of α1-adrenoceptor occupancy by endogenous norepinephrine during the treatment with milnacipran, fluvoxamine and imipramine to that without drug were estimated to be 7.13, 1.00 and 4.12, respectively. The α1-adrenoceptor occupancy by endogenous norepinephrine was increased in a dose-dependent manner by milnacipran, whereas fluvoxamine had essentially no effect. Conclusions: The piloerection observed after the replacement of fluvoxamine with milnacipran in this patient appears to have been due to an increase in the α1-adrenoceptor occupancy by endogenous norepinephrine induced by milnacipran. © 2007 The Authors.

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Possible mechanisms for the pharmacokinetic interaction between phenytoin and folinate in rats.

Yamasaki D, Tsujimoto M, Ohdo S, Ohtani H, Sawada Y*.

Therapeutic Drug Monitoring (Therapeutic Drug Monitoring) 22(3) ( 4 ) 162-168 - 411 2007.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 01634356

The plasma concentration of phenytoin (PHT) is decreased by coadministration of folinate (leucovorin; LV), a folate (FA) analogue. The aim of this study was to examine the effect of LV on the pharmacokinetics of PHT in rats in vivo and to investigate the mechanism of the interaction. LV (50 mg/kg) was administered orally to rats concomitantly given intravenous PHT (50 mg/kg) to evaluate the effect of LV on the pharmacokinetics of PHT. The effect of LV on the plasma protein binding of PHT was investigated by using plasma from rats that had received oral LV. We also examined the effects of LV on the uptake of PHT into isolated rat hepatocytes and on the metabolism of PHT in isolated rat hepatocytes and rat hepatic microsomes. LV significantly increased the systemic clearance (2-fold) and liver-to-blood partition coefficient (1.24-fold) of PHT. However, it did not affect the plasma protein binding or hepatic uptake of PHT. LV increased the metabolism of PHT in isolated rat hepatocytes, with a significant 1.41-fold increase in the maximum rate of metabolism and a decrease in the Michaelis-Menten constant. On the other hand, 5-methyltetrahydrofolate (5-MTHF), a primary metabolite of LV and FA, significantly increased p-hydroxylation of PHT in rat hepatic microsomes, whereas LV and FA themselves had no effect. In conclusion, these results suggest that, in rats, LV, an FA analogue, decreases the plasma concentration of PHT by increasing the hepatic metabolism of PHT, and the increase in the PHT metabolism is, at least in part, attributable to 5-MTHF. © 2007 Lippincott Williams & Wilkins, Inc.

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Development of a pharmacokinetic model to optimize the dosage regimen of TS-1, a combination preparation of tegafur, gimeracil and oteracil potassium.

Inoue S, Ohtani H, Tsujimoto M, Hori S, Sawada Y*.

Drug Metabolism and Pharmacokinetics (Drug metabolism and pharmacokinetics) 22(3) ( 3 ) 162-168 - 168 2007.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 13474367

BACKGROUND: TS-1 is a combination preparation of tegafur, a prodrug of 5-fluorouracil (5-FU), with gimeracil, a potent inhibitor of dihydropyrimidine dehydrogenase (DPD), which mediates the inactivation of 5-FU. UFT is a combination preparation of tegafur with uracil, which also inhibits DPD, though less potently; UFT has a higher content of tegafur than that in TS-1. We aimed to develop a pharmacokinetic model to describe the kinetics of tegafur and 5-FU after the administration of TS-1 and UFT. METHODS: We developed a model incorporating the inhibition of DPD by gimeracil and uracil, and fitted the model to the observed kinetics of tegafur and 5-FU after the administration of TS-1 and UFT. Then, we simulated the plasma 5-FU profiles in patients with renal dysfunction and those after replacement of TS-1 with UFT and compared them with the observed profiles. RESULTS: The developed model could appropriately describe the plasma concentration profiles of 5-FU and tegafur after the administration of TS-1 in patients with normal and impaired renal function. CONCLUSION: The developed model may be useful to optimize the dosage regimen of TS-1 under various clinical conditions.

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Kinetic analysis of the transport of salicylic acid, a nonsteroidal anti-inflammatory drug, across human placenta.

Shintaku K, Arima Y, Dan Y, Takeda T, Kogushi K, Tsujimoto M, Nagata H, Satoh S, Tsukimori K, Nakano H, Hori S, Ohtani H, Sawada Y*.

Drug Metabol Dispos (Drug Metabolism and Disposition) 35(5) ( 5 ) 772-778 - 778 2007.05

Research paper (scientific journal), Joint Work, Accepted, ISSN 00909556

The aim of this study was to develop a pharmacokinetic model to describe the transplacental transfer of drugs, based on the human placental perfusion study. The maternal and fetal sides of human placentas were perfused with salicylic acid together with antipyrine, a passive diffusion marker. The drug concentration in the placental tissue was determined at the end of perfusion. A compartment model consisting of maternal space, fetal intravascular space, and placental tissue was fitted to the observed concentration profiles of salicylic acid in the maternal and fetal effluents. The developed model could adequately explain the concentration profiles of salicylic acid in the effluents with influx clearances from maternal and fetal perfusates to placental tissue of 0.0407 and 0.0813 ml/min/g cotyledon and efflux rate constants from placental tissue to maternal and fetal perfusates (k2 and k3) of 0.0238 and 0.176 min-1, respectively. The kinetics of antipyrine was adequately described by assuming rapid equilibrium between fetal perfusate and placental tissue compartments. The influx plasma clearance from the maternal side (K″1) in humans was estimated by taking into account the protein binding. The K″1/k2 value of salicylic acid was 1.07 ml/g cotyledon and was larger than that of antipyrine (0.642 ml/g cotyledon). We evaluated the transplacental transfer kinetics of salicylic acid by human placental perfusion study with various perfusion protocols. Based on the data obtained, we developed a pharmacokinetic model, which should enable us to estimate the influx profile of drugs into umbilical arterial blood from the maternal plasma concentration profile. Copyright © 2007 by The American Society for Pharmacology and Experimental Therapeutics.

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Assessment of alpha1-adrenoceptor antagonists in benign prostatic hyperplasia based on the receptor occupancy theory.

Ito K, Ohtani H, Sawada Y*.

British Journal of Clinical Pharmacology 63(4) 394-403 2007.04

Research paper (scientific journal), Joint Work, Accepted

Effect of macrolide antibiotics on uptake of digoxin into rat liver.

Ito S, Nasu R, Tsujimoto M, Murakami H, Ohtani H, Sawada Y*.

Biopharmaceutics and Drug Disposition (Biopharmaceutics and Drug Disposition) 28(3) ( 3 ) 113-123 - 123 2007.04

Research paper (scientific journal), Joint Work, Accepted, ISSN 01422782

The objective of this study was to examine the effect of macrolide antibiotics, clarithromycin, erythromycin, roxithromycin, josamycin and azithromycin, on the hepatic uptake of digoxin. The uptake of [3 H]digoxin was studied in rats in vivo, using the tissue-sampling single-injection technique, and in isolated rat hepatocytes in vitro. The uptake of [3H]digoxin into rat hepatocytes was concentration-dependent with a Michaelis constant (Km) of 445 nM. All the macrolide antibiotics inhibited the uptake of [3H]digoxin into rat hepatocytes in a concentration-dependent manner. However, clarithromycin did not affect the in vivo hepatic uptake of digoxin in rats. The in vivo permeability-surface area product of digoxin for hepatic uptake (PSinf) was estimated to be 12.5 ml/min/g liver from the present in vitro data, which is far larger than the hepatic blood flow rate (1.4 ml/ min/g liver). Macrolide antibiotics at clinically relevant concentrations inhibit digoxin uptake by rat hepatocytes in vitro, but not in vivo, probably because hepatic uptake of digoxin in rats is blood flow-limited. Clinically observed digoxin-macrolide interaction in humans could be due to macrolide inhibition of hepatic digoxin uptake, if the uptake is permeation-limited. Copyright © 2007 John Wiley & Sons, Ltd.

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Assessment of α<inf>1</inf>-adrenoceptor antagonists in benign prostatic hyperplasia based on the receptor occupancy theory

Ito K., Ohtani H., Sawada Y.

British Journal of Clinical Pharmacology (British Journal of Clinical Pharmacology) 63 ( 4 ) 394 - 403 2007.04

ISSN 03065251

Aims: To assess the mechanistic relationship between doxazosin (α1-receptor antagonist) and receptor occupancy and a measure of pharmacological effect (Qmax, the maximum urinary flow rate) and to compare the mean receptor occupancy ratio at clinical doses of doxazosin, tamsulosin, terazosin and prazosin in benign prostatic hyperplasia (BPH). Methods: A ternary complex model, which described the mechanism of α1-receptor antagonists, was fitted to the pharmacological effects and receptor occupancy ratio data for doxazosin (standard tablet). In addition, mean receptor occupancy was calculated for other α1- receptor antagonists and the optimal receptor occupancy was evaluated. The clinical pharmacological effects of the controlled release formulation of doxazosin (doxazosin GITS) were estimated based on the receptor occupancy. Results: The mechanistic based model was able to describe the pharmacological effects of doxazosin. Regardless of the plasma concentrations or clinical dose of each drug, the results suggest that receptor occupancy is useful to assess quantitatively and compare the pharmacological effects of drugs with similar mechanisms of action. The clinical dosage for doxazosin GITS was estimated to be at least 8 mg and the stable pharmacological effect is expected based on the estimated receptor occupancy. Conclusions: A model for Qmax improvement in BPH based on the receptor occupancy theory was able to describe the clinical effects of the α1-receptor antagonists. Receptor occupancy is a useful index for predicting the clinical effects of α1-receptor antagonists. © 2006 The Authors.

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医薬品適正使用推進のためのWEBページを用いた薬剤師向けe-Learnigシステムの利用者による評価

佐田宏子, 大谷壽一, 矢崎泰三, 坂本浩己, 堀里子, 澤田康文

医薬品情報学 ((一社)日本医薬品情報学会) 8 ( 4 ) 307 - 314 2007.02

ISSN 1345-1464

e-Learningシステム(アリセプト処方せんチェックe-ラーニング)を構築した。構築・公開したe-Learningシステムの利用実態を把握するとともに、システムに対するユーザーの意見を調査した。会員薬剤師5766例に対して、電子メールで送信した。198件の回答が得られた。薬剤師としての経験年数が10年以上の薬剤師が約62%を占めた。開局薬局が67.7%であった。自己研鑚システムとして有用と評価され、継続したシステムの公開が期待されていると考えた。また、他の医薬品に関しても同様なシステムを望む回答者が多く、要望が多かった医薬品を対象に計画的に作成し、公開してゆくことが望ましいと考えられた。

薬薬連携に関するアンケート調査　疑義照会の現状と問題点

三木晶子, 堀里子, 大谷壽一, 澤田康文

医薬品情報学 ((一社)日本医薬品情報学会) 8 ( 4 ) 296 - 301 2007.02

ISSN 1345-1464

薬薬連携の中での疑義照会の現状と問題点を明らかにし、今後の疑義照会のあり方を探ることで適正な薬物治療を実施する上で有用な情報を構築することを目的にアンケート調査を行った。院外処方せんを発行する際に、処方鑑査を行っているかとの問いに関して、半数近くの47%が薬剤部の関与していないと回答した。院外処方せん発行後の〜次疑義照会先は薬剤部であるとの回答が74%を占め、一次疑義照会先を医師へ直接と決めている病院は12%にとどまった。保険薬局薬剤師の半数が、ほとんど近隣の医療機関からの処方せんを受けていると回答し、回答者の約98.5%が疑義照会の経験があると回答した。疑義照会先は、医師に電話(23.7%)、外来受付に電話、薬剤部に電話ほぼ同程度であった。疑義照会の内容としては、用法の不備、規格、単位の不備が大多数を占めた。

Antacid interaction with new quinolones: dose regimen recommendations based on pharmacokinetic modeling of clinical data for ciprofloxacin, gatifloxacin and norfloxacin and metal cations.

Miyata K, Ohtani H, Tsujimoto M, Sawada Y*.

International Journal of Clinical Pharmacology and Therapeutics 45(1) 63-70 2007.01

Research paper (scientific journal), Joint Work, Accepted

Antacid interaction with new quinolones: Dose regimen recommendations based on pharmacokinetic, model of clinical data for ciprofloxacin, gatifloxacin and norfloxacin and metal cations

Miyata K., Ohtani H., Tsujimoto M., Sawada Y.

International Journal of Clinical Pharmacology and Therapeutics (International Journal of Clinical Pharmacology and Therapeutics) 45 ( 1 ) 63 - 70 2007.01

ISSN 09461965

Objective: New quinolones (NQs) are wily used to treat various infections. However, concomitant oral administration of metal cations may decrease absorption of NQs and consequently decrease their blood concentration and pharmacological effect. A convenient approach to avoid this interaction is to separate the dosages by a certain interval. In this study, we aimed to develop a novel pharmacokinetic model to describe NQs-metal cation interactions in order to estimate the optimal dosing interval. Methods: Plasma concentration-time profiles of NQs after administration without or with metal cations at various dosing intervals were collected from the literature and analyzed with a pharmacokinetic model incorporating the formation ofNQs-metal cations complex. The model was fitted to the reported time profiles of ciprofloxacin (CPFX) plasma concentration after concomitant administration with aluminum hydroxide/ magnesium hydroxide antacid (Al/Mg antacid; Maalox, Maalox70) at various dosing intervals to obtain the pharmacokinetic parameters of CPFX. Model analysis was also carried out for gatifloxacin (GFLX) and norfloxacin (NFLX). Results: The developed model could adequately explain the interactions in all the combinations investigated. The model predicted, in the cases of usual doses of CPFX with Maalox, GFLX with Maalox70 and NFLX with sucralfate, that the NQ should be administered 4.5, 4.5 and 3.5 hours after, or 1, 1 and 0.5 hours before the administration of metal cations, respectively, to ensure 90% of control absorption. Conclusions: The developed model can adequately describe the extent of interaction between NQs and metal cations, and should be clinically useful to design dosage regimens to circumvent the interaction. © 2007 Dustri-Verlag Dr. K. Feistle.

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Inhibitory effects of angiotensin II receptor antagonists and leukotriene receptor antagonists on the transport of human organic anion transporter 4.

Yamashita F, Ohtani H, Koyabu N, Ushigome F, Satoh H, Murakami H, Uchiumi T, Nakamura T, Kuwano M, Tsujimoto M, Sawada Y*.

Journal of Pharmacy and Pharmacology (Journal of Pharmacy and Pharmacology) 58(11) ( 11 ) 1499-1505 - 1505 2006.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 00223573

Human organic anion transporter 4 (OAT4) is the only member of the OAT family that is expressed in the placenta and also expressed in kidney. Although OAT4 has been shown to transport certain organic anions as well as other members of the OAT family, fewer numbers of substrates have been identified for OAT4 compared with OAT1 and OAT3, suggesting that the substrate specificity of OAT4 is greater than other OAT members. However, the substrate specificity of OAT4 remains to be investigated in detail. The aim of this study was to examine the effects of various drugs on the OAT4-mediated transport of estrone-3-sulfate, a typical substrate of OAT4, by using human embryonic kidney cells stably transfected with OAT4 (HEK-OAT4). HEK-OAT4 cells exhibited concentration- dependent uptake of estrone-3-sulfate, with a Km value of 20.9±3.53 μM. Dehydroepiandrosterone sulfate and probenecid potently inhibited estrone-3-sulfate uptake. We also searched for the potential inhibitors of OAT4 and identified candesartan, candesartan cilexetil, losartan, losartan carboxyl (EXP3174) and valsartan as inhibitors of OAT4, with K i values of 88.9, 135.2, 24.8, 13.8 and 19.6 μM, respectively. The above angiotensin II receptor antagonists and leukotriene receptor antagonists share a common structural feature, that is the tetrazole group. Although pranlukast is devoid of anionic motifs other than the tetrazole group, it potently inhibited the OAT4-mediated uptake of estrone-3-sulfate, indicating that a tetrazole group may be one important structural feature in substrate recognition by OAT4. © 2006 The Authors.

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モルヒネ製剤の剤形変更時の薬剤師の対応に関する研究

久澄礼子, 大谷壽一, 堀里子, 澤田康文

医薬品情報学 ((一社)日本医薬品情報学会) 8 ( 3 ) 205 - 211 2006.11

ISSN 1345-1464

薬剤師に対するアンケート調査を実施し、モルヒネ製剤の剤形変更時の処方チェックや投与設計に関して、薬剤師がどのように対応したいと考えているか調査した。モルヒネ製剤の剤形変更時の処方設計を支援するための専用アプリケーションが必要であった。アンケート調査により、半数以上の薬剤師が、モルヒネ製剤の剤形変更時の処方チェックおよび投与設計を添付文書の用法・用量との照合、モルヒネ換算比・等鎮痛用量比との照合で行っていた。モルヒネ製剤の剤形変更時の処方チェックを薬物動態シミュレーション等に基づいて行いたいと考えているものの実践できていないことが示された。薬物動態シミュレーションに基づいた処方設計支援システムの構築は、薬剤師の現状の問題点を解決する有用な手段であることが示唆された。

適正な処方設計・調剤支援システムのための医薬品製剤情報の規格化

佐田宏子, 大谷壽一, 澤田康文

医療情報学 ((一社)日本医療情報学会) 26 ( 3 ) 209 - 215 2006.10

ISSN 0289-8055

処方設計支援や処方チェックシステムの構築にあたっては、医薬品情報は、システム上でテキストとして保持されているだけでは不十分であり、利用状況を考慮に入れた適正な規格化が行われている必要がある。本研究においては、医薬品の製剤特性に基づいた処方設計支援機能を提供するために必要な医薬品情報を抽出、整理するとともに、それらを規格化するための基準と、適正に保持できるデータベース(DB)の構造を設計することを目的とした。既存の医薬品102種について、製剤特性や剤形加工後の安定性などのデータを収集し、我々がすでに報告した処方チェックパターンと照合して解析することによって、最適なDBのフォーマットを設計するとともに、剤形加工の可否について、DBに収載するための規格化基準を作成した。設計したDB構造と規格化基準を、それらの設計や構築に用いた薬剤とは異なる既存の88種の医薬品に適用したところ、処方設計支援に必要な製剤特性情報をもらすことなく収載することができた。今回構築したDBは、医薬品の製剤特性情報を適正に保持し、処方薬に対する錠剤の粉砕などの可否をチェックするシステムに利用できると考えられた。今回設計した製剤特性・剤形加工DBは、処方チェックおよび処方設計支援システムの構築に有用な基盤を提供すると考えられる。(著者抄録)

Dosage adjustment of quinolone antibiotics and angiotensin-converting enzyme inhibitors in patients with renal dysfunction.

Ohtani H, Kinoshita Y, Nagasaki Y, Sata H, Miki A, Tsujimoto M, Sawada Y*.

International Journal of Clinical Pharmacology and Therapeutics (International Journal of Clinical Pharmacology and Therapeutics) 44(9) ( 9 ) 428-437 - 437 2006.09

Research paper (scientific journal), Joint Work, Accepted, ISSN 09461965

The aim of this study was to verify an approach for calculating pharmacokinetic parameters suitable for adjusting dosage regimens in patients with renal dysfunction. We carried out a retrospective analysis of the pharmacokinetic profiles of 12 new quinolone antibiotics and 11 angiotensin-converting enzyme inhibitors (ACEIs) in patients with normal and impaired renal function to obtain the renal excretion ratio (Rrenal) of each drug. We demonstrated that the pharmacokinetics of each drug in a patient with renal dysfunction can be adequately estimated using the Rrenal value of each drug together with the creatinine clearance as an index of the individual's renal function. Using the Rrenal value obtained, we could successfully simulate pharmacokinetic profiles of the drugs in publications other than that used to obtain the Rrenal values. On the other hand, age-related changes in the pharmacokinetics of new quinolone antibiotics are not always adequately predicted using the Rrenal value compared to using creatinine clearance alone as an index, and the reasons for this are not fully understood. These results demonstrate that dosage regimens of quinolone antibiotics and ACEIs in patients with renal dysfunction can be adequately optimized using the Rrenal value for each drug using the present approach. © 2006 Dustri-Verlag Dr. K. Feistle.

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Major determinant factors of the extent of interaction between grapefruit juice and calcium channel antagonists.

Ohnishi A, Ohtani H, Sawada Y*.

British Journal of Clinical Pharmacology (British Journal of Clinical Pharmacology) 62(2) ( 2 ) 196-199 - 199 2006.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 03065251

Aim: To evaluate quantitatively the influence of bioavailability and plasma unbound fraction (fu) on the extent of interaction between grapefruit juice (GFJ) and calcium antagonists. Methods: The extent of drug-GFJ interaction was evaluated from reported clinical interaction studies of 11 calcium antagonists. The relationship between extent of interaction and bioavailability or fu was analysed. Results: The following significant hyperbolic relationships were observed: [Extent] = 12.2/[bioavailability] + 1 and [Extent] = 0.718/[fu ] + 1. Conclusions: Bioavailability and fu are major determinant factors of calcium antagonist-GFJ interaction: a drug with smaller bioavailability or lower fu is likely to exhibit a more potent interaction, and vice versa. © 2006 Blackwell Publishing Ltd.

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服薬ノンコンプライアンス時の薬剤師の対応に関する実状と問題点

久澄礼子, 大谷壽一, 三木晶子, 堀里子, 澤田康文

医薬品情報学 ((一社)日本医薬品情報学会) 8 ( 2 ) 133 - 138 2006.08

ISSN 1345-1464

薬剤師間情報交換・研修システムに登録していた薬剤師4106名を対象に、電子メールを用いて患者のノンコンプライアンスへの対応に関するアンケート調査を行った。99.0%の薬剤師がノンコンプライアンス症例を経験し、そのうち75.5%が患者にノンコンプライアンス後の対処法を指示した経験があった。どのようにして対処法を決定したかについては、「次回から処方どおり服用するように指示した」が最も多く、「薬物動態シミュレーション等により血中濃度または薬効の経時的変化を計算して指示した」は2.6%のみであった。しかし、薬物動態シミュレーション等による投与設計で対応をしなかった薬剤師の57.5%が「対処法は適切だった」と回答した。対処法を決定する際の問題点については、「薬物動態シミュレーション等により対処すれば良いと考えたが、具体的な方法がわからなかった」が最も多く、問題点を解決するための要望については、「対処法について投与設計できるシステムが欲しい」が最も多かった。

処方オーダリングシステムの入力方法と操作性における問題点　医師に対するアンケート調査

佐田宏子, 大谷壽一, 折井孝男, 澤田康文

医療薬学 ((一社)日本医療薬学会) 32 ( 7 ) 679 - 685 2006.07

ISSN 1346-342X

医師を対象としたアンケート調査によって,処方オーダリングシステムの使用実態とその操作性に対する医師の意識を明らかにし,処方オーダリングシステムにおけるヒューマン・マシンインターフェース(HMI)が具備すべき要件を検討した.「薬剤師間情報交換・研修システム」の会員薬剤師の中から,病院薬剤師を抽出し,医師に対する処方オーダリングシステムについてのアンケート調査を行った.17医療施設中,9施設は処方薬の候補リストの表示に必要な入力文字数が2文字以下で,最低入力文字数をシステムによって3文字にすることが必要と考えられた.処方オーダリングシステム導入による弊害として,医薬品名の不確実な認識に起因する処方オーダリングミスの発生が危惧された.投与量チェックシステムは,否定的な意見は少なく,投薬ミス防止のため標準で具備すべき機能であると考えられた.特定服用時点の限定システムが組み込まれている施設は3施設であった

Pharmacokinetic modelling of the interaction between St John's wort and ciclosporin A.

Murakami Y, Tanaka T, Murakami H, Tsujimoto M, Ohtani H, Sawada Y*.

British Journal of Clinical Pharmacology (British Journal of Clinical Pharmacology) 61(6) ( 6 ) 671-676 - 676 2006.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 03065251

Aims: St John's wort (SJW) decreases the blood concentration of ciclosporin A (CsA), which may result in allograft rejection. In addition, the time course of this interaction is not parallel with the administration of SJW. We aimed to develop a pharmacokinetic model to predict the time profile of blood CsA concentrations during and after the intake of SJW. Methods: We developed a pharmacokinetic model incorporating turnover of detoxicating proteins, with the assumption that the amount of detoxicating proteins is in inverse proportion to the ratio of trough blood concentration to daily dose (C/D ratio) of CsA. First, we collected time profiles of blood CsA during and after the intake of SJW from the literature. Next, we analysed the relationship between D/C ratio and the daily dose of SJW at steady state. Subsequently, the developed model was simultaneously fitted to the time profiles of C/D ratios by using a nonlinear least-squares method to obtain model parameters. Results: The model analysis revealed that the induction of the detoxicating proteins by SJW was saturable with an elimination rate constant of the detoxicating proteins (ke) of 4.72 month-1. Elimination half-life of the detoxicating proteins calculated from the ke value was 4.4 days, suggesting that the dose of CsA should be carefully monitored for up to 2 weeks after the cessation of SJW intake. Conclusions: The present model may provide additional information for use in identifying optimal dosage regimens of CsA during and after the intake of SJW to prevent an adverse drug interaction between CsA and SJW. © 2006 Blackwell Publishing Ltd.

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The canine CYP1A2 deficiency polymorphism dramatically affects the pharmacokinetics of 4-cyclohexyl-1-ethyl-7-methylpyrido[2,3-D]-pyrimidine-2-(1H)-one (YM-64227), a phosphodiesterase type 4 inhibitor.

Tenmizu D, Noguchi K, Kamimura H, Ohtani H, Sawada Y*.

Drug Metabolism and Disposition (Drug Metabolism and Disposition) 34(5) ( 5 ) 800-806 - 806 2006.05

Research paper (scientific journal), Joint Work, Accepted, ISSN 00909556

In a previous study, it was shown that the novel canine single nucleotide polymorphism (SNP) CYP1A2 1117C>T yields an inactive enzyme. In this study, the effect that this SNP has on the pharmacokinetics of 4-cyclohexyl-1-ethyl-7- methylpyrido[2,3-d]pyrimidine-2-(1H)-one (YM-64227) was investigated. Plasma concentrations of the unchanged drug and five of its metabolites (MM-1 to MM-5) were determined after either intravenous or oral administration of YM-64227 to genotyped dogs (C/C, C/T, and T/T groups). Liver microsomes were prepared from these dogs to determine the in vitro metabolic clearance of YM-64227. After a single oral administration, the maximum plasma concentration and absolute bioavailability of YM-64227 in the T/T group were 17.1 times and 27.2 times higher than those in the C/C group, respectively, whereas the pharmacokinetics of YM-64227 after intravenous administration were not affected by genotype. The metabolic profiles in the T/T group were quite distinct from the others; i.e., the main metabolite was MM-2 in the C/C group, whereas MM-1 and MM-5 were the main metabolites in the T/T group. The formation clearances of MM-2 and MM-3 in the microsomes derived from T/T type dogs were significantly lower, whereas those of MM-1, MM-4, and MM-5 were not affected. A statistically significant correlation was observed between the in vivo and in vitro metabolic intrinsic clearances (r = 0.82, p < 0.001). The canine CYP1A2 1117C>T SNP proved to be responsible for a substantial portion of the interindividual variability in the pharmacokinetics of YM-64227. Copyright © 2006 by The American Society for Pharmacology and Experimental Therapeutics.

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WEBページを用いた薬剤師向け実践的知識修得型e-Learningシステムの開発

佐田宏子, 大谷壽一, 矢崎泰三, 坂本浩己, 堀里子, 澤田康文

医薬品情報学 ((一社)日本医薬品情報学会) 8 ( 1 ) 13 - 19 2006.05

ISSN 1345-1464

医薬品の取り違えミスを防止するための薬名類似度の定量的指標の構築

大谷壽一, 竹田正幸, 今田結城, 澤田康文

薬学雑誌 ((公社)日本薬学会) 126 ( 5 ) 349 - 356 2006.05

ISSN 0031-6903

投薬ミスを防止するために薬名の類似度を計数化することを試みた.2薬名間の共通文字列部分が長いほど類似度が高いと考え,断片パターン指標を応用した指標を導入した.「共通文字列の連続性」,「先頭・末尾部分の重要性」の係数を配分した指標1,これら2係数に更にカタカナの文字形状の類似性係数を導入した指標2,音韻の類似性係数を導入した指標3を構築した.実際に医薬品名の取り違えが生じた227例を正例とし,負例は無作為に作成した2270組を用いて指標の評価を行った.既に報告されている指標として,薬名の特徴をベクトル化したcos1,先頭・末尾2文字のみに着目したhtcoと比較した.指標1,2,3はいづれもcos1,htcoよりも優れた評価関数値を示し,特に指標2が最良であった.指標2の偽陽性率,偽陰性率はcos1よりも著しく改善された.この指標は薬名に基づく医療ミスを防止する上で重要な情報を提供すると考えられた

Effects of herbal extracts on the function of human organic anion-transporting polypeptide OATP-B.

Fuchikami H, Satoh H, Tsujimoto M, Ohdo S, Ohtani H, Sawada Y*.

Drug Metabolism and Disposition (Drug Metabolism and Disposition) 34(4) ( 4 ) 577-582 - 582 2006.04

Research paper (scientific journal), Joint Work, Accepted, ISSN 00909556

Most known interactions between herbal extracts and drugs involve the inhibition of drug-metabolizing enzymes, but little is yet known about the possible role of transporters in these interactions. In this study, we have examined the effects of herbal extracts used in dietary supplements on the function of organic anion-transporting polypeptide B (OATP-B; OATP2B1), which is expressed on human intestinal epithelial cells and is considered to be involved in the intestinal absorption of various drugs. Specifically, the effects of 15 herbal extracts on uptake of estrone-3-sulfate, a typical OATP-B substrate, by human embryonic kidney 293 cells stably expressing OATP-B were evaluated. At concentration levels considered likely to be attainable in the human intestine, extracts of bilberry, echinacea, green tea, banaba, grape seed, ginkgo, and soybean potently inhibited estrone-3-sulfate uptake by 75.5, 55.5, 82.1, 61.1, 64.5, 85.4, and 66.8%, respectively (P < 0.01). The inhibitory effect of ginkgo leaf extract was concentration-dependent (IC50 = 11.2 ± 3.3 μg/ml) and reversible. Moreover, flavonol glycosides and catechins significantly inhibited the function of OATP-B, suggesting that the inhibitory effects of the herbal extracts on OATP-B may be primarily attributable to flavonoids. The extracts of mulberry, black cohosh, and Siberian ginseng moderately (but significantly) inhibited estrone-3-sulfate uptake by 39.1, 47.2, and 49.2%, respectively (P < 0.05). Extracts of barley, Job's tears, rutin, rafuma, and passionflower were ineffective. These results suggest that coadministration of some dietary supplements may decrease the absorption of orally administered substrates of OATP-B. Copyright © 2006 by The American Society for Pharmacology and Experimental Therapeutics.

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Polymorphisms and linkage disequilibrium of the OATP8 (OATP1B3) gene in Japanese subjects.

Tsujimoto M, Hirata S, Dan Y, Ohtani H, Sawada Y*.

Drug Metabolism and Pharmacokinetics (Drug metabolism and pharmacokinetics) 21(2) ( 2 ) 165-169 - 169 2006.04

Research paper (scientific journal), Joint Work, Accepted, ISSN 13474367

OATP8, a member of the organic anion-transporting polypeptide family, is expressed on the sinusoidal membrane of hepatocytes, and transports endogenous organic anions, such as 17beta-glucuronosyl estradiol, and xenobiotic substances, such as digoxin. The objective of this study is to search for polymorphisms of the OATP8 gene and to assess the allele frequency of the polymorphisms in the Japanese population. Analysis of the OATP8 gene in 79 subjects revealed complete linkage of two deletion polymorphisms in the 5' regulatory region, deletion from position -28 to -11 and deletion from position -7 to -4, with an allele frequency of 0.196 for the deletion allele. The polymorphisms T334G (Ser112Ala) and G699A (Met233Ile) were also shown to be in complete linkage disequilibrium, with an allele frequency of 0.728 for the variant (112Ala/233Ile) allele. Interestingly, linkage disequilibrium was identified between the ins/del polymorphism and SNPs at 112 and 233. The predicted major haplotype was the insert-variant type with a haplotype frequency of 0.60.

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テガフール,ギメラシル,オテラシルカリウム3剤配合抗癌剤(ティーエスワン)の適正使用の実態調査とWeb e-learningシステムの構築

辻野靖彦, 佐田宏子, 杉山清子, 友永雄二, 三木晶子, 堀里子, 大谷壽一, 澤田康文

医薬品情報学 ((一社)日本医薬品情報学会) 7 ( 4 ) 293 - 299 2006.02

ISSN 1345-1464

薬剤師によるティーエスワンに関する疑義照会の実態調査を行った.ティーエスワンの処方箋を応需した薬剤師において禁忌や他のフッ化ピリミジンからの切り替え時の注意などに理解がなく疑義照会に至らない処方箋チェックがあり,薬剤師への的確な医薬品情報提供の必要性が示された.ティーエスワンの処方を応需し,より多くの薬剤師に医薬品情報を効率よく提供する方法として,より実践的に処方箋応需業務を支援することを目的に,インターネットを介した薬剤師を対象とするWeb e-learningシステム(EL)を構築し評価を加えた.ELを使用した薬剤師のほとんどが参考になったと回答しており,ELは医薬品情報を提供するうえで受講者の満足度を得られる有用なシステムであることが証明でき,時間的自由度,学習効果,受講者の満足度とも良好であった

Receptor occupancy-based analysis of the contributions of various receptors to antipsychotics-induced weight gain and diabetes mellitus.

Matsui-Sakata A, Ohtani H, Sawada Y*.

Drug Metabolism and Pharmacokinetics (Drug Metabolism And Pharmacokinetics) 20(5) ( 5 ) 368-378 - 378 2005.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 13474367

Summary: Objective: Among various adverse reactions of atypical antipsychotics, weight gain and impaired glucose tolerance are clinically significant. The aim of this study is to analyze quantitatively the contributions of various receptors to these antipsychotics-induced adverse reactions based on the receptor occupancy theory. Methods: Two indices of antipsychotics-induced weight gain (the values estimated by a metaanalysis and the observed values in clinical trials) and the morbidity rate of type 2 diabetes mellitus during treatment with antipsychotics were taken from the literature. We calculated the estimated mean receptor occupancies of α1adrenergic, α2adrenergic, dopamine D2, histamine H1, muscarinic acetylcholine (mACh), serotonin 5-HT1A, 5-HT2Aand 5-HT2Creceptors by antipsychotics by using the pharmacokinetic parameters and receptor dissociation constants, and analyzed the correlation between the occupancies and the extent of adverse reactions as assessed using the aforementioned indices. Results: There were statistically significant correlations between the estimated occupancies of H1and mACh receptors and antipsychotics-induced weight gain estimated by metaanalysis (rs= 0.81 and rs= 0.83, respectively, p<0.01). There were also statistically significant correlations between these receptor occupancies and observed weight gain in clinical trials (rs= 0.66 in each case, p<0.01). The morbidity rate of type 2 diabetes mellitus was highly correlated with H1, mACh, and 5-HT2Creceptor occupancies (rs= 0.90 in each case, p<0.05). However, H1receptor occupancy was also highly correlated with mACh receptor occupancy among antipsychotics, so that only one of them may be critically associated with the adverse reactions. Considering that these adverse reactions have not been reported for drugs with mACh receptor antagonistic action, other than antipsychotics, the H1receptor may contribute predominantly to the antipsychotics-induced weight gain and diabetes mellitus. Discussion/Conclusion: Model analysis based on receptor occupancy indicates that H1receptor blockade is the primary cause of antipsychotics-induced weight gain and diabetes mellitus. © 2005, The Japanese Society for the Study of Xenobiotics. All rights reserved.

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Functional characterization of human monocarboxylate transporter 6 (SLC16A5).

Murakami Y, Kohyama N, Kobayashi Y, Ohbayashi M, Ohtani H, Sawada Y, Yamamoto T*.

Drug Metabolism and Disposition (Drug Metabolism and Disposition) 33(12) ( 12 ) 1845-1851 - 1851 2005.09

Research paper (scientific journal), Joint Work, Accepted, ISSN 00909556

Human monocarboxylate transporter 6 (MCT6) has recently been isolated, and its tissue distribution has been established at the mRNA level, but its functional properties remain unknown. The aim of this study is to investigate the transport properties of MCT6. When expressed in Xenopus laevis oocytes, MCT6 transported [3H]bumetanide in a pH- and membrane potential-sensitive but not proton gradient-dependent manner, with the Kt value of 84 μM. Furthermore, MCT6 transported various drugs such as probenecid and nateglinide. Neither [14C]L-lactic acid nor [3H]L- tryptophan, typical substrates of other MCT isoforms, was transported by MCT6. Four loop diuretics, i.e., furosemide, piretanide, azosemide, and torasemide, thiazides, probenecid, glibenclamide, and nateglinide inhibited the MCT6-mediated uptake of [3H]bumetanide. In contrast, short-chain carboxylic acids, such as L-lactic acid and succinic acid did not inhibit the MCT6-mediated uptake of bumetanide. These results suggest that the substrate specificity of MCT6 is distinct from those of other MCTs. Bumetanide would be a good tool for investigating the functional properties of MCT6. It is probable that MCT6 is involved in the disposition of various drugs, including bumetanide. Copyright © 2005 by The American Society for Pharmacology and Experimental Therapeutics.

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Inhibitory effects of various beverages on ritodrine sulfation by recombinant human sulfotransferase isoforms SULT1A1 and SULT1A3.

Nishimuta H, Tsujimoto M, Ogura K, Hiratsuka A, Ohtani H, Sawada Y*.

Pharmaceutical Research (Pharmaceutical Research) 22(8) ( 8 ) 1406-1410 - 1410 2005.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 07248741

Purpose. Ritodrine is known to undergo extensive presystemic sulfation in the intestinal mucosa, and its bioavailability is as low as 30%. Accordingly, inhibition of intestinal sulfation may lead to an increase in the bioavailability of ritodrine. In this study, we aimed to investigate the activities of ritodrine sulfation by SULT1A1, which is expressed predominantly in the liver, and SULT1A3, which is expressed predominantly in the intestine, as well as the inhibitory effects of beverages on their activities. Methods. We investigated ritodrine sulfation by using recombinant human sulfotransferase (SULT) 1A1 and SULT1A3 in an in vitro study. Next, we investigated the inhibitory effects of grapefruit juice, orange juice, green tea, and black tea on ritodrine sulfation. Results. Sulfation of ritodrine by SULT1A3 was much higher than that by SULT1A1, suggesting that the bioavailability of ritodrine may be limited by intestinal SULT1A3. The ritodrine sulfation activities of SULT1A1 and SULT1A3 were significantly inhibited by all beverages examined at a concentration of 10%. Green tea and black tea exhibited potent inhibition; even at a concentration of 5%, they both inhibited SULT1A1 by 100% and SULT1A3 by ≥95%. Conclusion. Our results suggest that concomitant ingestion of beverages such as green tea and black tea may increase the bioavailability of orally administered ritodrine, and perhaps other β2-agonists, and lead to an increase in the clinical effects or adverse reactions. © 2005 Springer Science + Business Media, Inc.

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Functional analysis of organic cation transporter 3 expressed in human placenta.

Sata R, Ohtani H, Tsujimoto M, Murakami H, Koyabu N, Nakamura T, Uchiumi T, Kuwano M, Nagata H, Tsukimori K, Nakano H, Sawada Y*.

Journal of Pharmacology and Experimental Therapeutics (Journal of Pharmacology and Experimental Therapeutics) 315(2) ( 2 ) 888-895 - 895 2005.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 00223565

The aim of this study is to investigate the placental transport mechanism of cationic compounds by comparison of the uptake of an organic cation into human placental basal membrane vesicles (BLMVs) with that into organic cation transporter 3 (OCT3)-expressing cells. Reverse transcription-polymerase chain reaction analysis demonstrated that OCT3 is the only OCT isoform expressed in the human placenta. The function of OCT3 was investigated by measuring the uptake of 1-methyl-4-phenylpyridinium (MPP+) into human embryonic kidney (HEK)293 cells stably expressing OCT3 (HEK/OCT3 cells). The OCT3-mediated uptake of MPP+ was sodium- and chloride-independent and saturable, with a Michaelis constant (Km) of 82.5 μM. The OCT3-mediated uptake was inhibited by various cationic drugs in a concentration-dependent manner but not by anionic compounds, such as p-aminohippuric acid and captopril, or a zwitterion, carnitine. Western blotting analysis of membrane vesicles prepared from human term placenta revealed that OCT3 is expressed only in BLMVs but not in microvillous membrane vesicles. The uptake of MPP+ into BLMVs was membrane potential-dependent and saturable, with a Km value of 51.8 μM, which is similar to that in HEK293/OCT3 cells. The inhibitory spectrum of various compounds on MPP+ uptake by BLMVs was also similar to that in HEK293/OCT3 cells. These results suggest that OCT3 is expressed on the basal membrane of human trophoblast cells and plays an important role in the placental transport of cationic compounds. Copyright © 2005 by The American Society for Pharmacology and Experimental Therapeutics.

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Physiologically based pharmacokinetic model for pralmorelin hydrochloride in rats.

Nasu R, Kumagai Y, Kogetsu H, Tsujimoto M, Ohtani H, Sawada Y*.

Drug Metabolism and Disposition (Drug Metabolism and Disposition) 33(10) ( 10 ) 1488-1494 - 1494 2005.07

Research paper (scientific journal), Joint Work, Accepted, ISSN 00909556

Pralmorelin hydrochloride (pralmorelin), consisting of six amino acid residues, is a growth hormone-releasing peptide. The aim of this study is to analyze the pharmacokinetics of pralmorelin after intravenous bolus administration to rats, and to develop a physiologically based pharmacokinetic (PB-PK) model to describe and predict the concentrations of pralmorelin in blood and tissues. Pralmorelin (3 mg/kg) was administered intravenously to 24 Sprague-Dawley rats. Groups of three rats were sacrificed by decapitation at each designated time point (up to 4 h), and plasma and tissues (brain, lung, heart, liver, kidney, small intestine, muscle, adipose, and skin) were collected. Bile was also pooled until decapitation. The concentration of pralmorelin in samples was determined by liquid chromatography-tandem mass spectrometry. Plasma concentrations of pralmorelin declined rapidly in a biexponential manner. Biliary excretion of pralmorelin was so rapid that 80% of the dose was recovered unchanged in the bile within 1 h after administration. The distribution parameters in each tissue were obtained by using a hybrid model and an integration plot. They revealed that the distribution of pralmorelin into liver was blood flow-limited, and its distribution was permeability-limited in all other tissues. The PB-PK model developed in this study well described the time courses of pralmorelin concentration in the blood and tissues of rats. Copyright © 2005 by The American Society for Pharmacology and Experimental Therapeutics.

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Pharmacokinetic-pharmacodynamic analysis of antipsychotics-induced extrapyramidal symptoms based on receptor occupancy theory incorporating endogenous dopamine release.

Matsui-Sakata A, Ohtani H, Sawada Y*.

Drug Metabolism and Pharmacokinetics (Drug metabolism and pharmacokinetics) 20(3) ( 3 ) 187-199 - 199 2005.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 13474367

We aimed to analyze the risks of extrapyramidal symptoms (EPS) induced by typical and atypical antipsychotic drugs using a common pharmacokinetic-pharmacodynamic (PK-PD) model based on the receptor occupancy. We collected the data for EPS induced by atypical antipsychotics, risperidone, olanzapine and quetiapine, and a typical antipsychotic, haloperidol from literature and analyzed the following five indices of EPS, the ratio of patients obliged to take anticholinergic medication, the occurrence rates of plural extrapyramidal symptoms (more than one of tremor, dystonia, hypokinesia, akathisia, extrapyramidal syndrome, etc.), parkinsonism, akathisia, and extrapyramidal syndrome. We tested two models, i.e., a model incorporating endogenous dopamine release owing to 5-HT2A receptor inhibition and a model not considering the endogenous dopamine release, and used them to examine the relationship between the D2 receptor occupancy of endogenous dopamine and the extent of drug-induced EPS. The model incorporating endogenous dopamine release better described the relationship between the mean D2 receptor occupancy of endogenous dopamine and the extent of EPS than the other model, as assessed by the final sum of squares of residuals (final SS) and Akaike's Information Criteria (AIC). Furthermore, the former model could appropriately predict the risks of EPS induced by two other atypical antipsychotics, clozapine and ziprasidone, which were not incorporated into the model development. The developed model incorporating endogenous dopamine release owing to 5-HT2A receptor inhibition may be useful for the prediction of antipsychotics-induced EPS.

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Functional induction and de-induction of P-glycoprotein by St. John's wort and its ingredients in a human colon adenocarcinoma cell line.

Tian R, Koyabu N, Morimoto S, Shoyama Y, Ohtani H, Sawada Y*.

Drug Metabolism and Disposition (Drug Metabolism and Disposition) 33(4) ( 4 ) 547-554 - 554 2005.04

Research paper (scientific journal), Joint Work, Accepted, ISSN 00909556

Continuous use of St. John's wort decreases the bioavailabilities of a variety of drugs. This interaction is attributed to the induction of cytochrome P450 3A4 and/or P-glycoprotein. In this study, we aimed to examine the chronic effects of St. John's wort and its constituents, hyperforin and hypericin, on the expression and function of P-glycoprotein in an intestinal cell line, LS 180. We also examined the acute inhibitory effect of St. John's wort on P-glycoprotein by using LLC-GA5-COL150 cells, which overexpress P-glycoprotein. St. John's wort and hyperforin but not hypericin increased the expression of P-glycoprotein in LS 180 cells. Removal of St John's wort resulted in a restoration of P-glycoprotein level within 48 h. The content of hyperforin in St. John's wort extract was high enough to induce P-glycoprotein, suggesting that the induction of P-glycoprotein by St. John's wort can be almost attributable to hyperforin. The LS 180 cells chronically exposed to St. John's wort or hyperforin exhibited the increase in the function of P-glycoprotein assessed by the efflux of digoxin, and the activities correlated well with P-glycoprotein level. On the other hand, St. John's wort and its two constituents did not show any acute effect on P-glycoprotein-mediated transport of digoxin. St John's wort induced P-glycoprotein in vitro that functions as a drug efflux pump. Hyperforin is considered to be a primary cause of the inductive effect of St. John's wort. Long-term administration of St. John's wort may cause clinically significant decrease in the plasma concentrations of P-glycoprotein substrates. Copyright © 2005 by The American Society for Pharmacology and Experimental Therapeutics.

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Association between neuroleptic drug-induced extrapyramidal symptoms and dopamine D2-receptor polymorphisms in Japanese schizophrenic patients.

Nakazono Y, Abe H, Murakami H, Koyabu N, Isaka Y, Nemoto Y, Murata S, Tsutsumi Y, Ohtani H, Sawada Y*.

International Journal of Clinical Pharmacology and Therapeutics 43(4) 163-171 2005.04

Research paper (scientific journal), Joint Work, Accepted

Citrus juices inhibit the function of human organic anion-transporting polypeptide OATP-B.

Satoh H, Yamashita F, Tsujimoto M, Murakami H, Koyabu N, Ohtani H, Sawada Y*.

Drug Metabolism and Disposition (Drug Metabolism and Disposition) 33(4) ( 4 ) 518-523 - 523 2005.04

Research paper (scientific journal), Joint Work, Accepted, ISSN 00909556

Human organic anion-transporting polypeptide B (OATP-B; OATP2B1) is expressed in the human intestinal epithelial cells, and is suggested to be involved in the intestinal absorption of anionic drugs in vivo. Although citrus juices have been shown to inhibit the function of human OATP-A (OATP1A2), the effect of citrus juices on the OATP-B function remains unclear. In this study, we aimed to examine the effects of citrus juices on the function of OATP-B. The effects of citrus juices on the uptake of estrone-3-sulfate, a typical substrate for OATP-B, into human embryonic kidney 293 cells stably expressing OATP-B were evaluated. Juices were diluted with uptake buffer, adjusted to pH 7.4 and approximately 300 mOsm, and used for the experiments. Grapefruit juice (GFJ) and orange juice (OJ) at a concentration of 5% significantly inhibited the OATP-B-mediated uptake of estrone-3-sulfate by 82 and 53%, respectively. Major constituents of GFJ and OJ also significantly inhibited the OATP-B-mediated uptake of estrone-3-sulfate. Glibenclamide, a hypoglycemic drug, was identified for the first time as a substrate for OATP-B with a Kt value of 6.26 μM. GFJ and OJ inhibited the OATP-B-mediated uptake of glibenclamide. These results suggest that citrus juices may inhibit the intestinal absorption of anionic drugs, such as glibenclamide, via the inhibition of OATP-B. Copyright © 2005 by The American Society for Pharmacology and Experimental Therapeutics.

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Improvement of dry mouth by replacing paroxetine with fluvoxamine.

Arima Y, Kubo C, Tsujimoto M, Ohtani H, Sawada Y*.

Annals of Pharmacotherapy (Annals of Pharmacotherapy) 39(3) ( 3 ) 567-571 - 571 2005.02

Research paper (scientific journal), Joint Work, Accepted, ISSN 10600280

OBJECTIVE: To present a case of improvement of paroxetine-induced dry mouth by substitution of fluvoxamine and analyze this case based on receptor occupancy theory. CASE SUMMARY: A 66-year-old woman with major depressive disorder had been treated with brotizolam 0.5 mg/day, flunitrazepam 2 mg/day, sulpiride 100 mg/day, bromazepam 2 mg/day, trazodone 25 mg/day, and paroxetine hydrochloride 10 mg/day. Although her psychological symptoms improved gradually, she complained of dry mouth. Paroxetine was replaced with fluvoxamine maleate 50 mg/day, and the dryness disappeared within a month. DISCUSSION: We calculated the time courses of muscarinic acetylcholine (mACh) receptor occupancy after oral administration of paroxetine and fluvoxamine at the treatment doses by using pharmacokinetic parameters obtained from the literature. The mACh receptor occupancy was estimated to be decreased from 0.22% to 0.020% by replacing paroxetine with fluvoxamine. CONCLUSIONS: The improvement of dry mouth observed after the replacement of paroxetine with fluvoxamine in this patient may have been due to a decrease in the mACh receptor occupancy.

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Functional characterization of adenosine transport across the BBB in mice.

Murakami H, Ohkura A, Takanaga H, Matsuo H, Koyabu N, Naito M, Tsuruo T, Ohtani H, Sawada Y*.

International Journal of Pharmaceutics (International Journal of Pharmaceutics) 290(1-2) ( 1-2 ) 37-44 - 44 2005.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 03785173

We investigated transport characteristics of adenosine across the blood-brain barrier (BBB) in mice. Uptake clearance across the BBB was measured by using an in situ mouse brain perfusion technique and cultured mouse brain capillary endothelial cell line (MBEC4 cells). Nucleoside transporter was cloned by RT-PCR and expressed on Xenopus laevis oocyte. Both in situ and in vitro studies revealed that the adenosine uptake is concentration-dependent, Na +-independent and S-(p-nitrobenzyl)-6-thioinosine (NBMPR)-sensitive. The Kt values of in situ and in vitro studies were 31.7 ± 13.8 μM and 11.9 ± 2.84 μM, respectively. A good correlation was found for the inhibitory effects of nucleoside analogs to adenosine uptake between in situ and in vitro studies. RT-PCR revealed the expression of RNA of mouse equilibrative nucleoside transporter (mENT1) in mouse brain capillary and MBEC4 cells. In mENT1 expressed on X. laevis oocyte, Kt value of adenosine transport was 6.9 ± 2.7 μM (and comparable to those in situ and in vitro studies). In conclusion, we characterized the adenosine transport across the BBB in mice by using in situ brain perfusion technique and MBEC4 cells and found that these transports share common characteristics with mENT1-mediated transport. Transport of adenosine across the BBB in mice may be attributable to mENT1. © 2004 Elsevier B.V. All rights reserved.

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Interactions between clarithromycin and digoxin in patients with end-stage renal disease.

Hirata S, Izumi S, Furukubo T, Ota M, Fujita M, Yamakawa T, Hasegawa I, Ohtani H, Sawada Y*.

International Journal of Clinical Pharmacology and Therapeutics (International Journal of Clinical Pharmacology and Therapeutics) 43(1) ( 1 ) 30-36 - 36 2005.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 09461965

Objective: To report a significant increase in the serum levels of digoxin associated with the use of clarithromycin in six patients undergoing renal replacement therapy. Case summary: All six patients were males with end-stage renal disease and in need of renal replacement therapy. Four patients were anuric. The mean age was 78.8 ± 5.8 (66-83) years. All patients except one, who was treated by hemofiltration, were treated by hemodialysis. All patients except one, who had been treated with metildigoxin (0.35 mg/week), were also taking digoxin (0.375 mg/week). Clarithromycin was administered at a dose of 200 - 400 mg/day for the treatment of bronchitis in all patients. The concomitant administration of clarithromycin increased serum digoxin levels from 1.8 - 4.0-fold in all cases. In two of six cases, a high probability of digoxin intoxication and suspicion of digoxin intoxication was evident. In three of six cases, serum digoxin levels increased within 12 days after the co-administration of clarithromycin, while in the other three cases, serum digoxin levels were increased 53 - 190 days after the administration of clarithromycin. Conclusion: The simultaneous administration of clarithromycin caused an increase in digoxin levels in six patients undergoing renal replacement therapy. The increase in the serum digoxin can be attributed to the inhibition of P-glycoprotein in the intestine and/or bile capillary rather than the kidney by clarithromycin since renal function was dramatically impaired, and four of the patients were anuric. The issue of why serum digoxin levels were increased so late in three patients undergoing renal replacement is unclear. However, this interaction seemed to be clinically significant even in ESRD patients, whose renal function was highly impaired. The simultaneous use of digoxin and clarithromycin sbould be avoided even in patients undergoing renal replacement therapy whose renal function is impaired, since digoxin levels may increase unexpectedly. ©2005 Dustri-Verlag Dr. K. Feistle.

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Association between neuroleptic drug-induced extrapyramidal symptoms and dopamine D<inf>2</inf>-receptor polymorphisms in Japanese schizophrenic patients

Nakazono Y., Abe H., Murakami H., Koyabu N., Isaka Y., Nemoto Y., Murata S., Tsutsumi Y., Ohtani H., Sawada Y.

International Journal of Clinical Pharmacology and Therapeutics (International Journal of Clinical Pharmacology and Therapeutics) 43 ( 4 ) 163 - 171 2005

ISSN 09461965

The aim of the present study is to examine the relationship between dopamine D2-receptor gene (DRD2) polymorphisms (Taq1A, Taq1B, -141C Ins/Del) and the risk of extrapyramidal adverse effects (EPS), assessed according to the Drug-Induced Extra-Pyramidal Symptoms Scale (DIEPSS), or the maintenance dose of antipsychotics in schizophrenic patients. The DIEPSS score was significantly higher in patients bearing the -141C Del allele than in those without it. Taq1A and Taq1B restriction fragment length polymorphisms (RFLPS) did not significantly affect the DIEPSS score. On the other hand, maintenance doses of neuroleptics and antiparkinsonian drugs were significantly higher in patients with the B1 allele of Taq1B RFLP than in those without it, while the Taq1A RFLP and -141C Ins/Del polymorphisms were not significantly related to the maintenance doses. In conclusion, the risk of EPS may be increased in patients with the -141C Del allele of the DRD2 gene. In these patients, antipsychotics should be administered with caution. ©2005 Dustri-Verlag Dr. K. Feistle.

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Effects of grapefruit juice and orange juice components on P-glycoprotein- and MRP2-mediated drug efflux

Honda Y., Ushigome F., Koyabu N., Morimoto S., Shoyama Y., Uchiumi T., Kuwano M., Ohtani H., Sawada Y.

British Journal of Pharmacology (British Journal of Pharmacology) 143 ( 7 ) 856 - 864 2004.12

ISSN 00071188

1 We investigated the effects of grapefruit juice (GFJ) and orange juice (OJ) on drug transport by MDR1 P-glycoprotein (P-gp) and multidrug resistance protein 2 (MRP2), which are efflux transporters expressed in human small intestine. 2 We examined the transcellular transport and uptake of [ 3H]vinblastine (VBL) and [ 14C]saquinavir in a human colon carcinoma cell line (Caco-2) and in porcine kidney epithelial cell lines transfected with human MDR1 cDNA and human MRP2 cDNA, LLC-GA5-COL150, and LLC-MRP2, respectively. 3 In Caco-2 cells, the basal-to-apical transports of [ 3H]VBL and [ 14C]saquinavir were greater than those in the opposite direction. The ratio of basal-to-apical transport to apical-to-basal transport of [ 3H]VBL and [ 14C]saquinavir by Caco-2 cells was reduced in the presence of MK571 (MRPs inhibitor), verapamil (P-gp inhibitor), cyclosporin A (inhibitor of both), 50% ethyl acetate extracts of GFJ and OJ, or their components (6′,7′-dihydroxybergamottin, bergamottin, tangeretin, hepatomethoxyflavone, and nobiletin). 4 Studies of transport and uptake of [ 3H]VBL and [ 14C]saquinavir with MDR1 and MRP2 transfectants showed that VBL and saquinavir are transported by both P-gp and MRP2. GFJ and OJ components inhibited the transport by MRP2 as well as P-gp. However, their inhibitory potencies for P-gp or MRP2 were substrate-dependent. 5 The present study has revealed that GFJ and OJ interact with not only P-gp but also MRP2, both of which are expressed at apical membranes and limit the apical-to-basal transport of VBL and saquinavir in Caco-2 cells.

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Treatment of gastric hemorrhage by pulverized omeprazole and antacid - Concomitant administration via a nasogastric tube

Yamaguchi T., Mukai S., Kinoshita E., Ohtani H., Sawada Y.

International Journal of Clinical Pharmacology and Therapeutics (International Journal of Clinical Pharmacology and Therapeutics) 42 ( 11 ) 594 - 596 2004.11

ISSN 09461965

Gastroesophageal reflux (GER) is a common episode in pediatric patients with severe motor and intellectual disabilities (SMID) and occasionally leads to a severe clinical state accompanied with nausea, hematemesis, melena, wheezing, pneumonia, anemia and/or failure to thrive. We report here a case of a 14-year-old male with Lennox syndrome who had been treated with a histamine H2 blocker intravenously or via a nasogastric tube for repeated gastric hemorrhage due to severe GER. Since his gastric hemorrhage became resistant to the H2 blocker, we decided to replace it with a proton pump inhibitor (PPI). Although lansoprazole can be decapsulated for administration via a nasogastric tube, it tends to block fine tubes. The acid-sensitive drug omeprazole, another oral PPI, is commercially available as enteric-coated tablets. Therefore, we pulverized the tablets and administered omeprazole, mixed with a small amount of antacid, via a nasogastric tube. The patient's gastric hemorrhage was dramatically improved. Thus, administration of pulverized omeprazole concomitantly with antacid via a fine nasogastric tube may provide a novel approach for the treatment of chronic GER in pediatric patients with SMID. © 2004 Dustri-Verlag Dr. K. Feistle.

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Inhibitory effects of pomelo on the metabolism of tacrolimus and the activities of CYP3A4 and P-glycoprotein

Egashira K., Ohtani H., Itoh S., Koyabu N., Tsujimoto M., Murakami H., Sawada Y.

Drug Metabolism and Disposition (Drug Metabolism and Disposition) 32 ( 8 ) 828 - 833 2004.08

ISSN 00909556

We recently reported a case of increase in the blood level of tacrolimus following intake of pomelo in a renal transplant recipient. To clarify the mechanism of this increase in the blood level of tacrolimus, we investigated the effect of pomelo juice extract on the activities of CYP3A4 and P-glycoprotein, in comparison with that of extract of grapefruit juice (GFJ). The 10% ethyl acetate extracts of the juice of three pomelos of different origins (Banpeiyu, pomelo I; Hirado Buntan, pomelo II; and Tosa Buntan, pomelo III) and GFJ significantly inhibited 6β-hydroxylation of testosterone in human liver microsomes by 76.4, 67.2, 37.5, and 83.9%, respectively. The extract of pomelo I was as potent as that of GFJ. The metabolism of tacrolimus itself was also inhibited by the extract of pomelo I, as well as that of GFJ. Furthermore, the inhibition of both 6β-hydroxylation of testosterone and metabolism of tacrolimus by pomelo I and GFJ was preincubation time-dependent. On the other hand, the extract of pomelo I had little effect on the transcellular transport of tacrolimus or [3H]digoxin across a monolayer of LLC-GA5-COL150 cells (a porcine kidney epithelial cell line, LLC-PK1, transfected with human MDR1 cDNA and over-expressing human P-glycoprotein). In conclusion, pomelo constituents inhibit the activity of CYP3A4 and may thereby produce an increase in the blood level of tacrolimus.

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Various dosing weights and correction to serum digoxin assays in hemodialysis patients

Hirata S., Uenishi K., Izumi S., Furukubo T., Ota M., Fujita M., Yamakawa T., Ohtani H., Sawada Y.

Journal of Pharmacy Technology (Journal of Pharmacy Technology) 20 ( 4 ) 221 - 225 2004.07

ISSN 87551225

Background: Digoxin is distributed in skeletal muscles in high concentrations. The most reliable parameter to measure the distribution of digoxin in patients undergoing hemodialysis is not known. Objective: To estimate which distribution parameter-estimated lean body mass (E-LBM) calculated by subtracting the fat mass from the dry weight, lean body mass, dry weight, and ideal body weight - is the most reliable predictor for assessing the accuracy of a digoxin dosing regimen in patients undergoing hemodialysis. Methods: A retrospective study was conducted to evaluate 21 patients undergoing hemodialysis who were administered digoxin. The patients were divided into 2 groups: digoxin 0.125 mg administered twice a week (low-dose group) or 3 times per week (high-dose group). The differences between E-LBM, lean body mass, dry weight, and ideal body weight for the low- and high-dose groups were determined. The relationships between serum digoxin concentrations and the weekly digoxin dose per E-LBM, lean body mass, dry weight, and ideal body weight were also determined. Results: E-LBM, lean body mass, dry weight, and ideal body weight in the high-dose group were significantly larger than those in the low-dose group (p = 0.021, 0.015, 0.024, and 0.0029, respectively), although no significant difference in serum digoxin concentrations was evident. Significant correlation was found between serum digoxin concentrations and the weekly digoxin dosage per E-LBM, dry weight, lean body mass, and ideal body weight (r = 0.746, p < 0.0001; r = 0.638, p = 0.0014; r = 0.645, p < 0.0011; r = 0.553, p = 0.0083, respectively). Conclusions: E-LBM appears to reflect the best parameter for predicting serum digoxin concentrations. The use of the dry weight parameter could be generally useful for adjusting the dosage of digoxin in patients undergoing hemodialysis.

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Effect of hematocrit on pharmacokinetics of tacrolimus in adult living donor liver transplant recipients

Minematsu T., Sugiyama E., Kusama M., Hori S., Yamada Y., Ohtani H., Sawada Y., Sato H., Takayama T., Sugawara Y., Makuuchi M., Iga T.

Transplantation Proceedings (Transplantation Proceedings) 36 ( 5 ) 1506 - 1511 2004.06

ISSN 00411345

Objective Plasma drug concentrations are generally considered to reflect efficacy and pharmacokinetics more directly than those in whole blood. However, whole blood has been selected as the matrix to monitor concentrations of tacrolimus (FK506), because it is difficult to accurately measure plasma FK506 concentrations. Because FK506 highly and saturably binds in blood cells, a change in hematocrit value (Hct) may affect FK506 pharmacokinetics. Therefore, we investigated effects of Hct on FK506 pharmacokinetics. Methods First, we analyzed data on FK506 distribution among human blood cells in vitro. Briefly, we employed an equation, which describes saturable binding of FK506 to blood cells, and simulated plasma FK506 concentrations and clearances using the above equation with respect to a variable Hct. Subsequently, we retrospectively analyzed dosages and whole blood FK506 concentrations to predict plasma FK506 concentrations in living donor transplant recipients. Results In the simulation study, the Hct changed plasma FK506 concentrations and clearances based in whole blood. In living donor liver transplant recipients, whole blood FK506 concentrations were maintained within a therapeutic range, while the Hct varied after transplantation. The correlation of Hct with the ratio of dose/trough concentrations of FK506 (D/C) in plasma (D/Cp) (R = -0.23, n = 343) was weaker than that for D/C in whole blood (D/CWB) (R = -0.53, n = 343). Conclusion Hct may be an important factor affecting the pharmacokinetics of FK506 in living donor liver transplantation recipients. It may be necessary to take Hct into consideration in the FK506 dosing regimen, especially when the Hct is low.

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塩酸ドネペジルの臨床における使用の実態　薬剤師に対するアンケート調査

児玉裕克, 大谷壽一, 澤田康文

医療薬学 ((一社)日本医療薬学会) 30 ( 6 ) 413 - 419 2004.06

ISSN 1346-342X

「インターネットを用いた薬剤師間情報交換・研修システム」を介して,塩酸ドネペジルの添付文書に規定されている用法・用量から逸脱した症例を確認した.中でも「初回から3mgあるいは5mg未満の量で1〜2週間後も継続されている」という,有効性が期待できない用量での処方が最も多く認められた.アンケート調査の結果および河野らの報告を考慮すると,3mg/日以下の投与量で有効で,かつ副作用が軽減される患者が存在する可能性は高いが,現段階では,医療用添付文書に定められた用法および用量を遵守する必要があり,規定外の投与は推奨できない.よって,臨床試験により,血中濃度と治療効果の関係を明らかにするとともに,低用量における治療効果を評価する必要性が示唆された

Tolbutamide Uptake Via pH- and Membrane-potential-dependent Transport Mechanism in Mouse Brain Capillary Endothelial Cell Line

Koyabu N., Takanaga H., Matsuo H., Ohtani H., Sawada Y., Naito M., Tsuruo T.

Drug Metabolism And Pharmacokinetics (Drug Metabolism And Pharmacokinetics) 19 ( 4 ) 270 - 279 2004.02

ISSN 13474367

Summary: The purpose of this study was to investigate the transport mechanism of tolbutamide across the blood-brain barrier (BBB) using MBEC4 cells as an in vitro BBB model. Methods: The BBB transport of tolbutamide was studied by using a mouse brain capillary endothelial cell line, MBEC4, cultured on dishes with their luminal membrane facing the culture medium. Results: The uptake of [14Cltolbutamide by MBEC4 cells was dependent on temperature and energy. The uptake coefficient of [14C]tolbutamide increased markedly with decreasing pH of the external medium from neutral to acidic. Valinomycin and replacement of chloride with sulfate or gluconate significantly increased the initial uptake of [14C]tolbutamide, while replacement with nitrate significantly decreased it. The uptake was significantly reduced by a proton ionophore, FCCP, and an anion-exchange inhibitor, DIDS. The initial uptake of [14C]tolbutamide was saturable with Kt of 0.61 ± 0.03 mM (pH 7.4) and 1.76±0.19 mM (pH 6.5). At pH 6.5, the initial uptake of [14C]tolbutamide was significantly reduced by several sulfa drugs, salicylic acid, valproic acid and probenecid, and was competitively inhibited by sulfaphenazole (Ki = 3.47 ±0.50 mM) and valproic acid (Ki = 2.29 ±0.43 mM). Conclusion: These observations indicate the existence of a pH-and membrane-potential-dependent anion exchange and/or proton-cotransport system(s) for concentrative uptake of tolbutamide and sulfa drugs in MBEC4 cells. © 2004, The Japanese Society for the Study of Xenobiotics. All rights reserved.

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Decreased Phenobarbital Absorption with Charcoal Administration for Chronic Renal Failure

Tanaka C., Yagi H., Sakamoto M., Koyama Y., Ohmura T., Ohtani H., Sawada Y.

Annals of Pharmacotherapy (Annals of Pharmacotherapy) 38 ( 1 ) 73 - 76 2004.01

ISSN 10600280

OBJECTIVE: To report a case of impaired absorption of orally administered phenobarbital associated with the concomitant administration of activated charcoal, and recovery of the absorption after administration of the 2 drugs was separated by a 1.5-hour interval. CASE SUMMARY: A 78-year-old woman, weighing 50 kg, who had undergone brain surgery was prescribed phenobarbital 120 mg/day for postoperative convulsions. Her serum phenobarbital concentration reached 24.8 μg/mL (therapeutically effective level 10-30). Thereafter, her renal function worsened, and activated charcoal 6 g/day was started. Four months after the start of activated charcoal, blood analysis revealed that the serum phenobarbital concentration was as low as 4.3 μg/mL. The phenobarbital dose was increased to 150 mg/day. Further evaluation revealed that activated charcoal and phenobarbital had been administered concomitantly. The dosage regimen was altered to separate the administration of the agents by at least 1. 5 hours. Subsequently, the patient's serum phenobarbital concentration increased to 11.9 μg/mL within 3 weeks. Her serum phenobarbital concentration was measured monthly thereafter and remained stable in the range of 14.8-18.6 μg/mL. DISCUSSION: Our patient's low serum phenobarbital concentration was considered likely to have been due to impaired gastrointestinal absorption of phenobarbital as a result of adsorption of phenobarbital on the activated charcoal. An objective causality assessment showed that the interaction was probable. CONCLUSIONS: Administration of activated charcoal and phenobarbital should be separated by an interval of at least 1.5 hours.

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Basal membrane localization of MRP1 in human placental trophoblast

Nagashige M., Ushigome F., Koyabu N., Hirata K., Kawabuchi M., Hirakawa T., Satoh S., Tsukimori K., Nakano H., Uchiumi T., Kuwano M., Ohtani H., Sawada Y.

Placenta (Placenta) 24 ( 10 ) 951 - 958 2003.11

ISSN 01434004

The placental trophoblast is considered to act as a barrier between mother and fetus, mediating the exchange of various materials across the placenta. ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp) and multidrug-resistance protein (MRP) are expressed in the placenta and function as efflux transport systems for xenobiotics. In the present study, we aimed to determine the localization of MRP1 in the human placenta in comparison with that of P-gp. Western blotting analysis with human placental membrane vesicles indicated that P-gp and MRP1 are localized on the brush-border membranes and basal membranes, respectively. Immunohistochemical analysis with human normal full-term placenta showed that anti-P-gp monoclonal antibody F4 stained the brush-border side of the trophoblast cells, whereas anti-MRP1 monoclonal antibody MRPr1 stained the basal side. These results confirm that P-gp and MRP1 are located on the brush-border membranes and basal membranes, respectively, of human full-term placental trophoblast. MRP1 was also detected on the abluminal side of blood vessels in the villi. Accordingly, MRP1 may play a role distinct from that of P-gp, which is considered to restrict the influx of xenobiotics into the fetus. © 2003 Elsevier Ltd. All rights reserved.

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In vivo delivery of glial cell-derived neurotrophic factor across the blood-brain barrier by gene transfer into brain capillary endothelial cells

Jiang C., Koyabu N., Yonemitsu Y., Shimazoe T., Watanabe S., Naito M., Tsuruo T., Ohtani H., Sawada Y.

Human Gene Therapy (Human Gene Therapy) 14 ( 12 ) 1181 - 1191 2003.08

ISSN 10430342

The gene encoding mouse glial cell-derived neurotrophic factor (mGDNF gene) was transfected into brain capillary endothelial cells (BCECs) with the aim of delivering the gene product extensively into the brain parenchyma by making use of the secretory function of BCECs. First, we transfected mGDNF gene into cultured BCECs (MBEC4; mouse brain capillary endothelial cells) in vitro. The amount of mGDNF protein secreted from the transfected cells into the medium was 1500 to 3200 pg/mg of cell protein per day, being about sevenfold higher than that accumulated intracellularly. Furthermore, the basolateral-directed secretion of mGDNF protein from the transfected MBEC4 cells was fivefold higher than the apical-directed secretion. Next, the hemagglutination virus of Japan (HVJ)-liposomes encapsulating mGDNF gene were administered to rats in vivo via the internal carotid artery. The transfected rats showed a marked increase in the brain level of GDNF as assessed by means of enzyme-linked immunosorbent assay (ELISA) and Western blotting on day 3 after the administration, and the level remained significantly elevated for at least 12 days. Furthermore, immunohistochemical staining revealed an increase in GDNF immunoreactivity throughout the transfected forebrain. These results indicate that the gene was successfully transferred in vivo from HVJ-liposomes into BCECs, where it was expressed, and the gene product was secreted into the brain. Then, using this delivery method, we evaluated the protective effect for dopamine neuron against a retrograde 6-hydroxydopamine (6-OHDA) lesion, as assessed by behavioral and neurochemical indices.

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Betaxolol-induced deterioration of asthma and a pharmacodynamic analysis based on β-receptor occupancy

Miki A., Tanaka Y., Ohtani H., Sawada Y.

International Journal of Clinical Pharmacology and Therapeutics (International Journal of Clinical Pharmacology and Therapeutics) 41 ( 8 ) 358 - 364 2003.08

ISSN 09461965

Objective: To report a case of deterioration of asthma associated with continuous use of oral betaxolol, a β1-selective β-blocking agent. We also analyzed the pharmacokinetics in this case by applying a receptor occupancy model. Case summary: A 68-year-old woman taking 5 mg of betaxolol for hypertension occasionally experienced asthmatic coughing after upper respiratory tract infection. Two years after the start of betaxolol, her asthma gradually worsened. Although pharmacotherapy for asthma was introduced, betaxotol was continued. Finally, she was admitted to hospital with bronchospasm. When she was discharged after 2 months, betaxolol was discontinued and losartan potassium (25 mg/d) was initiated instead for her hypertension. Since then, she has been free from bronchospasm. Method: We calculated the mean receptor occupancy (Φss) of the β1- and β2-receptors after the usual oral dose of betaxolol by using pharmacokinetic-pharmacodynamic parameters obtained from the literature. We estimated the decrease in the exercise pulse rate or the forced expiratory volume in 1 second (FEV1) by applying the Φss values to the model previously reported by us. Results: Betaxolol seems less likely than other β1-blocking agents to cause pulmonary adverse effects. However, the estimated decrease in FEV1 after oral administration of betaxolol (5 mg) was close to that after oral bisoprolol (5 mg), which has been reported to induce asthma. Conclusions: Oral betaxolol may induce bronchospasm, although betaxolol is considered to be highly cardioselective and seems less likely than other β1-selective blocking agents to cause pulmonary adverse effects. Betaxolol should be administered with caution to patients with asthma or chronic pulmonary disease.

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Inhibitory effect of erythromycin on potassium currents in rat ventricular myocytes in comparison with disopyramide

Hanada E., Ohtani H., Hirota M., Uemura N., Nakaya H., Kotaki H., Sato H., Yamada Y., Iga T.

Journal of Pharmacy and Pharmacology (Journal of Pharmacy and Pharmacology) 55 ( 7 ) 995 - 1002 2003.07

ISSN 00223573

Disopyramide, a class la antiarrhythmic agent, has been reported to induce torsades de pointes (TdP) associated with excessive QT prolongation in electrocardiogram (ECG), especially when concomitantly administered with erythromycin, a macrolide antibiotic agent. In this study, we have evaluated the effects of erythromycin on action potential duration (APD) and potassium currents in rat ventricular myocytes in comparison with disopyramide. We have evaluated the relationship between in-vitro potassium current inhibition and in-vivo QT prolongation observed in a previous study. Action potentials and membrane potassium currents, including delayed rectifier current (IK) and transient outward current (Ito), were recorded using a whole-cell patch clamp method in enzymatically-dissociated ventricular cells. Erythromycin and disopyramide prolonged APD in a concentration-dependent manner. Disopyramide (10-100 μM) and erythromycin (100 μM) led to increases in the APD at 90% repolarization level. Disopyramide reduced IK (IC50 = 37.2 ± 0.17 μM) and Ito (IC50 = 20.9 ± 0.13 μM) while erythromycin reduced IK (IC50 = 60.1 ± 0.29 μM) but not Ito. The observed prolongation of APD might be ascribed to the inhibition of potassium currents. Erythromycin produced the prolongation of APD and the inhibition of potassium currents with a lag time after addition of the drugs, which suggested that erythromycin might not reach potassium channels from outside the ventricular cells. The potency of disopyramide was almost equivalent under in-vitro and in-vivo conditions. However, potency of erythromycin in-vitro was far weaker than that in-vivo reported in a previous study, presumably due to a difference in the uptake of erythromycin into ventricular myocytes between in-vivo and in-vitro conditions. Therefore, when drug-induced risks of QT prolongation are to be evaluated, the difference of potencies between in-vitro and in-vivo should be taken into consideration.

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Pomelo-induced increase in the blood level of tacrolimus in a renal transplant patient

Egashira K., Fukuda E., Onga T., Yogi Y., Matsuya F., Koyabu N., Ohtani H., Sawada Y.

Transplantation (Transplantation) 75 ( 7 ) 1057 2003.04

ISSN 00411337

Background. Tacrolimus, an immunosuppressive agent, is widely used in patients after transplantation to prevent allograft rejection. Because tacrolimus has a narrow therapeutic range, it is essential to carefully control the blood level. It has been demonstrated that tacrolimus is metabolized mainly by cytochrome P-450 (CYP) 3A4, and that tacrolimus is a substrate of P-glycoprotein. Methods. This article reports a case of considerable increase in the blood level of tacrolimus after the intake of pomelo in a renal transplant recipient. Results. Pomelo may increase the blood concentration of tacrolimus by inhibiting CYP 3A4, P-glycoprotein, or both. Conclusions. Patients taking drugs such as tacrolimus or cyclosporine, which have their kinetics affected by grapefruit juice, should avoid pomelo and other grapefruit-related citrus fruits.

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Potentiation of domperidone-induced catalepsy by a P-glycoprotein inhibitor, cyclosporin A

Tsujikawa K., Dan Y., Nogawa K., Sato H., Yamada Y., Murakami H., Ohtani H., Sawada Y., Iga T.

Biopharmaceutics and Drug Disposition (Biopharmaceutics and Drug Disposition) 24 ( 3 ) 105 - 114 2003.04

ISSN 01422782

The distribution of domperidone (DOM), a peripheral dopamine D2 receptor antagonist, to the brain is restricted by P-glycoprotein (P-gp) at the blood-brain barrier (BBB) and for this reason, DOM rarely causes parkinsonian symptoms, such as extrapyramidal side effects (EPS), unlike other dopamine D2 antagonists. In this study, we aimed to investigate whether cyclosporin A (CsA), a P-gp inhibitor, potentiates EPS induced by DOM. The intensity of EPS was assessed in terms of the duration of catalepsy in mice. D1, D2 and mACh receptor occupancies at the striatum were measured in vivo and in vitro. Moreover, the distribution of DOM to the brain was investigated by using an in situ brain perfusion technique. The intensity of DOM-induced catalepsy was significantly potentiated by the coadministration of CsA. The in vivo occupancies of D1, D2 and mACh receptors, as well as the brain distribution of DOM, were increased by CsA. These results suggest that CsA increases the brain distribution of DOM by inhibiting P-gp at the BBB, and potentiates catalepsy by increasing the occupancies of the D1 and D2 receptors. The risk of DOM-induced parkinsonism may be enhanced by the coadministration of CsA. Copyright © 2003 John Wiley & Sons, Ltd.

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Kinetic analysis of P-glycoprotein-mediated transport by using normal human placental brush-border membrane vesicles

Ushigome F., Koyabu N., Satoh S., Tsukimori K., Nakano H., Nakamura T., Uchiumi T., Kuwano M., Ohtani H., Sawada Y.

Pharmaceutical Research (Pharmaceutical Research) 20 ( 1 ) 38 - 44 2003.01

ISSN 07248741

Purpose. P-Glycoprotein (Pgp) plays an important role in drug disposition and excretion in various tissues such as the brain, intestine, and kidney. Moreover, we have demonstrated that Pgp is expressed on the brush-border membranes of trophoblast cells in the placenta and restricts drug transfer from the maternal circulation to the fetus. However, the transport kinetics of physiologically expressed Pgp has scarcely been investigated. Methods. In this study, we assessed the functional kinetics of transport mediated by Pgp that is physiologically expressed in normal tissue by using human placental brush-border membrane vesicles (BBMVs). Digoxin and vinblastine were used as typical substrates of Pgp. Results. The uptakes of [3H] digoxin and [3H] vinblastine into BBMVs were significantly increased in the presence of an ATP-regenerating system. The ATP-dependent uptakes of [3H]digoxin and [3H] vinblastine into BBMVs exhibited saturable kinetics. The Michaelis constants (Kt values) were 2.65 ± 1.80 μM and 21.9 ± 3.37 μM, respectively. In the presence of a Pgp inhibitor such as verapamil, cyclosporine A, or progesterone, the ATP-dependent uptakes of [3H]digoxin and [3H] vinblastine into BBMVs were significantly reduced. Anti-Pgp monoclonal antibody C219 completely inhibited the uptake of [3H] digoxin. Conclusions. The transport kinetics of [3H]digoxin and [3H]vinblastine by physiologically expressed Pgp were successfully evaluated by using BBMVs prepared from normal human placenta. The present method enabled us to evaluate the function of physiologically expressed Pgp and is superior to the use of cultured transfectants in terms of the yield of vesicles. The present method may also be applicable to investigating the influence of various factors such as the genotype of the MDR1 gene or various pathophysiologic states of neonates on the function of Pgp.

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Agranulocytosis possibly caused by ranitidine in a patient with renal failure

Takami N., Yamamoto Y., Matsuo H., Ohtani H., Sawada Y.

International Journal of Clinical Pharmacology and Therapeutics (International Journal of Clinical Pharmacology and Therapeutics) 40 ( 11 ) 520 - 523 2002.11

ISSN 09461965

A 70-year-old Japanese woman with renal dysfunction under hemodialysis presented with vomiting and chill with fever. Over the previous 24 weeks she had been taking 75 mg of ranitidine after hemodialysis. Other medications taken were prednisolone, furosemide, α-calcidol, amlodipine and calcium carbonate. Before starting ranitidine, she had been treated with famotidine for about 2 years without complication. Hematological inspection on admission revealed agranulocytosis with WBC of 400/mm3. Ranitidine was discontinued and granulocyte colony-stimulating factor (G-CSF) was started. On Day 3, laboratory data showed slight improvement of cytopenia with WBC Of 1,000/mm3. On Day 6, her hemogram showed marked improvement with WBC of 11,700/mm3 and G-CSF was discontinued. She was discharged on Day 10. Several cases describing ranitidine-induced cytopenia are associated with the use of ranitidine at a dose of 150 mg/day or higher, and adverse reactions were found within 2 - 35 days after beginning ranitidine treatment. In the case described here, however, the adverse reaction occurred after a longer treatment period with ranitidine at a lower dose. In conclusion, ranitidine should be administered with great caution to patients with severe renal dysfunction.

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Nightmares and panic disorder associated with carvedilol overdose

Maebara C., Ohtani H., Sugahara H., Mine K., Kubo C., Sawada Y.

Annals of Pharmacotherapy (Annals of Pharmacotherapy) 36 ( 11 ) 1736 - 1740 2002.11

ISSN 10600280

OBJECTIVE: To report a case of nightmares and sleep disorder associated with improper use of carvedilol, an α/β-blocker, and to model the time course of receptor occupancy in this patient. CASE SUMMARY: A 41-year-old man with panic disorder had been treated with alprazolam 1.2 mg/d (3 times daily), carvedilol 10 mg/d (once in the morning), and etizolam 0.5 mg (for anxiety attack). Although the physical and psychological symptoms gradually improved, he reported nightmares and panic attacks. An interview revealed that he had been taking carvedilol 5 mg twice a day after lunch and dinner on his own initiative, in addition to the prescribed dosage. The patient was asked to take carvedilol 10 mg only after breakfast, as had been advised. Consequently, the sleep disorder and nightmares disappeared. METHODS: We calculated the time courses of β2-adrenoceptor binding occupancy in the central nervous system after oral administration of carvedilol with the ordinary and improper regimens by using pharmacokinetic/pharmacodynamic parameters obtained from the literature. RESULTS: Compared with the ordinary dose of carvedilol 10 mg once a day, the improper regimen (10 mg after breakfast followed by 5 mg after lunch and dinner) increases the β2-adrenoceptor binding occupancy at night (2300) to as high as the mean β2-adrenoceptor binding occupancy after an ordinary dose of propranolol. CONCLUSIONS: The sleep disorder and nightmares experienced by this patient had been induced by elevation of central β2-adrenoceptor binding occupancy at night as the result of improper use of carvedilol.

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非循環系薬物による致死性心電学的副作用の定量的予測法の確立

大谷壽一

上原記念生命科学財団研究報告集 ((公財)上原記念生命科学財団) 16 30 - 32 2002.11

薬物による催不整脈作用をin vitroの実験から定量的に予測するために,動物実験におけるin vivo-in vitro相関の解析と,ヒトカリウムチャンネル発現系におけるカリウム電流阻害作用と臨床的報告に基づく副作用リスクとの解析を試みた.モルモットを用い,in vivo実験系として心電図の薬物動態・動力学的解析を,in vitro実験系としては摘出心臓還流標本における心電図測定を行い,両者の関係を解析した.in vivo実験ではキニジン(30mg/kg/h),ソタロール(5mg/kg/h)のいずれによっても心電図QTc間隔は最大30-40msec程度延長した.in vitro実験でもQTcはいずれの薬剤でも延長し,灌流液濃度とQTc延長との関係は直線関係が認められた.いずれの薬剤でもin vivoではin vitroよりもQTc延長の強度が強いことが明らかとなった.従って,in vitro実験結果をin vivoに外挿する場合には,両者の濃度的乖離を十分に考慮する必要があると考えられた

Functional characterization of mouse cation transporter mOCT2 compared with mOCT1

Kakehi M., Koyabu N., Nakamura T., Uchiumi T., Kuwano M., Ohtani H., Sawada Y.

Biochemical and Biophysical Research Communications (Biochemical and Biophysical Research Communications) 296 ( 3 ) 644 - 650 2002.10

ISSN 0006291X

We characterized the function of mouse organic cation transporter OCT2 (TC 2.A.19.1.5) in comparison with that of OCT1 (TC 2.A.19.1.1). Uptake of [3H]1-methyl-4-phenylpyridinium ([3H]MPP+) by Xenopus laevis oocytes injected with mOCT1 (Slc22a1) or mOCT2 (Slc22a2) cRNA was attenuated by an increase of extracellular K+ concentration and under acidic extracellular conditions. The uptakes of [3H]MPP+ via mOCT1 and mOCT2 were saturable, with similar Michaelis constants (Kt) of 10 and 24 μM, respectively. mOCT2 also mediated the uptake of [14C]tetraethylammonium with a Kt value of 36 μM, which is similar to that of mOCT1. Quinine, tetraethylammonium, cimetidine, procainamide, choline, and N′-methylnicotinamide inhibited the uptake of [3H]MPP+ via mOCT1, as well as via mOCT2, and the inhibitory potencies for mOCT1 were comparable to but slightly higher than those for mOCT2. Thus, although the transport properties of mOCT2 are similar to those of mOCT1 in respect to the membrane-potential dependency, pH-sensitivity, and affinities for MPP+ and tetraethylammonium, several organic cations had weaker inhibitory effects on [3H]MPP+ uptake by mOCT2 than by mOCT1. © 2002 Elsevier Science (USA). All rights reserved.

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Transport and uptake of nateglinide in Caco-2 cells and its inhibitory effect on human monocarboxylate transporter MCT1

Okamura A., Emoto A., Koyabu N., Ohtani H., Sawada Y.

British Journal of Pharmacology (British Journal of Pharmacology) 137 ( 3 ) 391 - 399 2002.10

ISSN 00071188

1 Nateglinide, a novel oral hypoglycemic agent, rapidly reaches the maximum serum concentration after oral administration, suggesting that it is rapidly absorbed in the gastrointestinal tract. The aim of this work is to clarify the intestinal absorption mechanism of nateglinide by means of in vitro studies. 2 We examined the transcellular transport and the apical uptake of [ 14C]nateglinide in a human colon carcinoma cell line (Caco-2). We also examined whether nateglinide is transported via monocarboxylate transport-1 (MCT1) by means of an uptake study using MCT1-expressing Xenopus laevis oocytes. 3 In Caco-2 cells, the transcellular transport of [ 14C]nateglinide from the apical to basolateral side was greater than that in the opposite direction. The uptake of [ 14C]nateglinide from the apical side was concentration-dependent, H +-dependent, and Na +-independent. Kinetic analysis revealed that the Kt and Jmax values of the initial uptake rate of [ 14C]nateglinide were 448 μM and 43.2 nmol mg protein -1 5 min -1, respectively. Various monocarboxylates, including salicylic acid and valproic acid, and glibenclamide significantly inhibited the uptake of [ 14C]nateglinide. 4 The uptake study using MCT1-expressing oocytes showed that nateglinide inhibits the MCT1-mediated uptake of [ 14C]L-lactic acid, though nateglinide itself is not transported by MCT1. 5 Taken together, these results suggest that the uptake of nateglinide from the apical membranes of Caco-2 cells is, at least in part, mediated by a proton-dependent transport system(s) distinct from MCT1.

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Characteristics of L-lactic acid transport in basal membrane vesicles of human placental syncytiotrophoblast

Inuyama M., Ushigome F., Emoto A., Koyabu N., Satoh S., Tsukimori K., Nakano H., Ohtani H., Sawada Y.

American Journal of Physiology - Cell Physiology (American Journal of Physiology - Cell Physiology) 283 ( 3 52-3 ) C822 - 30 2002.09

ISSN 03636143

The characteristics of L-lactic acid transport across the trophoblast basal membrane were investigated and compared with those across the brush-border membrane by using membrane vesicles isolated from human placenta. The uptake of L-[14C]lactic acid into basal membrane vesicles was Na+ independent, and an uphill transport was observed in the presence of a pH gradient ([H+]out > [H+]in). L-[14C]lactic acid uptake exhibited saturation kinetics with a Km value of 5.89 ± 0.68 mM in the presence of a pH gradient. p-Chloromercuribenzenesulfonate and α-cyano-4-hydroxycinnamate inhibited the initial uptake, whereas phloretin or 4,4′-diisothiocyanostilbene-2,2′-disulfonate did not. Mono- and dicarboxylic acids suppressed the initial uptake. In conclusion, L-lactic acid transport in the basal membrane is H+ dependent and Na+ independent, as is also the case for the brush-border membrane transport, and its characteristics resemble those of monocarboxylic acid transporters. However, there were several differences in the effects of inhibitors between basal and brush-border membrane vesicles, suggesting that the transporter(s) involved in L-lactic acid transport in the basal membrane of placental trophoblast may differ from those in the brush-border membrane.

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Contribution of P-glycoprotein to efflux of ramosetron, a 5-HT<inf>3</inf> receptor antagonist, across the blood-brain barrier

Yamamoto C., Murakami H., Koyabu N., Takanaga H., Matsuo H., Uchiumi T., Kuwano M., Naito M., Tsuruo T., Ohtani H., Sawada Y.

Journal of Pharmacy and Pharmacology (Journal of Pharmacy and Pharmacology) 54 ( 8 ) 1055 - 1063 2002.08

ISSN 00223573

In-situ rat and mouse brain perfusion data indicated that the brain distribution of ramosetron (R-ramosetron), a 5-hydroxytryptamine3 (5-HT3) receptor antagonist, was extremely low compared with that expected from its lipophilicity. We hypothesized the involvement of an efflux system(s) and investigated the contribution of P-glycoprotein to efflux transport of ramosetron across the blood-brain barrier by means of an in-vitro uptake study in cell lines that over-express P-glycoprotein. We examined the contribution of mdr1a, mdr1b and MDR1 P-glycoprotein by using LV500 cells, MBEC4 cells and LL-GA5-COL300 cells, which over-express mdr1a P-glycoprotein, mdr1b P-glycoprotein and MDR1 P-glycoprotein, respectively. The uptake of [14C]ramosetron by LV500 cells and LLC-GA5-COL300 cells was significantly lower than that by the respective parental cells. Next, we studied the effects of P-glycoprotein inhibitors, verapamil and ciclosporin, on uptake of [14C] ramosetron by these cell lines. The uptake of [14C]ramosetron by LV500 cells and LLC-GA5-COL300 cells was significantly increased in the presence of verapamil or ciclosporin, while verapamil did not affect the uptake of [14C]ramosetron by MBEC4 cells. These results indicate that the efflux of [14C]ramosetron is partly mediated by mdr1a P-glycoprotein, but not by mdr1b P-glycoprotein, and that there is a difference in substrate specificity between mdr1a P-glycoprotein and mdr1b P-glycoprotein. Further, [14C]ramosetron was confirmed to be effluxed by human MDR1 P-glycoprotein. We conclude that the limited distribution of ramosetron to the brain is due, at least in part, to efflux mediated by the P-glycoprotein at the blood-brain barrier.

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Role of human MDR1 gene polymorphism in bioavailability and interaction of digoxin, a substrate of P-glycoprotein

Kurata Y., Ieiri I., Kimura M., Morita T., Irie S., Urae A., Ohdo S., Ohtani H., Sawada Y., Higuchi S., Otsubo K.

Clinical Pharmacology and Therapeutics (Clinical Pharmacology and Therapeutics) 72 ( 2 ) 209 - 219 2002.08

ISSN 00099236

Objective: Our objective was to quantitate the contribution of the genetic polymorphism of the human MDR1 gene to the bioavailability and interaction profiles of digoxin, a substrate of P-glycoprotein. Methods: The pharmacokinetics of digoxin was studied in 15 healthy volunteers, who were divided into 3 groups (n = 5 each) on the basis of genotyping for the MDR1 gene, in a 4-dose study after single doses of digoxin alone (0.5 mg orally and intravenously) and coadministered with clarithromycin (400 mg orally for 8 days). The dose of digoxin was reduced during the clarithromycin phase (0.25 mg orally and intravenously). Results: The bioavailability of digoxin in G/G2677C/C3435, G/T2677C/T3435, and T/T2677T/T3435 subjects were 67.6% ± 4.3%, 80.9% ± 8.9%, and 87.1% ± 8.4%, respectively, and the difference between G/G2677C/C3435 and T/T2677T/T3435 subjects was statistically significant (P < .05). The MDR1 variants were also associated with differences in disposition kinetics of digoxin, with the renal clearance being almost 32% lower in T/T2677T/T3435 subjects (1.9 ± 0.1 mL/min per kilogram) than G/G2677C/C3435 subjects (2.8 ± 0.3 mL/min per kilogram), and G/T2677C/T3435 subjects having an intermediate value (2.1 ± 0.6 mL/min per kilogram). Coadministration of clarithromycin did not consistently affect digoxin clearance or renal clearance. However, a significant increase in digoxin bioavailability was observed in G/G2677C/C3435 subjects (67.6% ± 4.3% versus 85.4% ± 6.1%; P < .05) but not in the other 2 genotype groups. Conclusion: The allelic variants in the human MDR1 gene are likely to be associated with altered absorption and/or disposition profiles of digoxin and P-glycoprotein-mediated drug interaction.

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Transluminal gene transfer into brain capillary endothelial cells in vivo with HVJ-liposomes

Jiang C., Matsuo H., Koyabu N., Ohtani H., Fujimoto H., Yonemitsu Y., Kaneda Y., Naito M., Tsuruo T., Sawada Y.

Journal of Drug Targeting (Journal of Drug Targeting) 10 ( 4 ) 345 - 352 2002.07

ISSN 1061186X

Bioactive proteins or peptides cannot be effectively delivered into brain capillary endothelial cells (BCECs) or brain parenchyma. In this study, we selectively transferred Escherichia coli β-galactosidase gene (β-gal) as a model gene into BCECs by using the hemagglutination virus of Japan (HVJ)-liposomes. HVJ-liposomes encapsulating a β-gal plasmid were used to transfect MBEC4 cells in vitro, and were administrated via the internal carotid artery to rat in vivo. Success of the procedure was confirmed by the detection of 116 kDa β-gal protein in transfected MBEC4 cells and in brain capillaries isolated from transfected rats, by Western blot analysis and histological staining. The enzymatic activities of β-galactosidase were 5- to 10-fold and 20-fold higher than when β-gal-containing liposomes without fusogenic activity (uncoated liposomes) or plasmid alone were employed in vitro and in vivo, respectively. Thus, HVJ-liposomes were demonstrated to be a useful vector to transfer a foreign gene into the brain capillary endothelium in vivo via the transluminal route.

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Distribution of domperidone into the rat brain is increased by brain ischaemia or treatment with the P-glycoprotein inhibitor verapamil

Dan Y., Murakami H., Koyabu N., Ohtani H., Sawada Y.

Journal of Pharmacy and Pharmacology (Journal of Pharmacy and Pharmacology) 54 ( 5 ) 729 - 733 2002.05

ISSN 00223573

Domperidone (DOM), a peripheral dopamine D2 receptor antagonist, is a substrate of P-glycoprotein (P-gp). Therefore, the transport of DOM into the brain may be restricted by P-gp function at the blood-brain barrier, and when the function of P-gp is impaired by ATP depletion under conditions of brain ischaemia (e.g. cerebral thrombosis), side-effects may be induced as a result of increased distribution of DOM into the brain. In this study, we investigated the effects of brain ischaemia and verapamil, a P-gp inhibitor, on the permeability coefficient-surface area product (PS values) of DOM across the blood-brain barrier by using an in-situ rat brain perfusion technique. The PS values of DOM were increased 3.4- and 3.6-fold after brain ischaemia for 10 and 20 min, respectively. Furthermore, co-administration of verapamil significantly increased the PS values of DOM by 42.6- and 43.3-fold in the normal and ischaemia groups, respectively. Brain vascular volume was not affected by ischaemia or verapamil. These results show that the transport of DOM into the brain is restricted by P-gp and that the brain distribution of DOM can be increased by cerebral ischaemia or co-administration of a P-gp inhibitor.

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Inhibition of P-glycoprotein by flavonoid derivatives in adriamycin-resistant human myelogenous leukemia (K562/ADM) cells

Ikegawa T., Ohtani H., Koyabu N., Juichi M., Iwase Y., Ito C., Furukawa H., Naito M., Tsuruo T., Sawada Y.

Cancer Letters (Cancer Letters) 177 ( 1 ) 89 - 93 2002.03

ISSN 03043835

We investigated the effects of natural flavones, quercetin and morin, and their pentamethyl, pentaethyl, pentapropyl, pentabutyl and pentaallyl ethers, on the function of P-glycoprotein (P-gp) assessed by an increase in the uptake of [3H]vincristine by human myelogenous leukemia (K562) cells and adriamycin-resistant human myelogenous leukemia (K562/ADM) cells. Pentamethyl, pentaethyl, pentapropyl and pentaallyl ethers of morin and quercetin (20 μM) all increased the uptake of [3H]vincristine by K562/ADM cells, while quercetin, morin and their pentabutyl ethers had no effect. Pentamethylquercetin, pentaallylquercetin and pentaethylmorin remarkably increased the uptake of [3H]vincristine by K562/ADM cells by 10.6, 10.8 and 14.4-fold, respectively. These inhibitory potencies for P-gp were more potent than typical P-gp inhibitors, cyclosporine A and verapamil. Taking into consideration that these flavonoid derivatives possess antitumor promoter activity, they may become candidates of effective multidrug resistance-reversing agents in cancer chemotherapy. © 2002 Elsevier Science Ireland Ltd. All rights reserved.

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Proton gradient-dependent transport of valproic acid in human placental brush-border membrane vesicles

Nakamura H., Ushigome F., Koyabu N., Satoh S., Tsukimori K., Nakano H., Ohtani H., Sawada Y.

Pharmaceutical Research (Pharmaceutical Research) 19 ( 2 ) 154 - 161 2002.03

ISSN 07248741

Purpose. To investigate the transport mechanism of valproic acid across the human placenta, we used human placental brush-border membrane vesicles and compared them with that of lactic acid. Methods. Transport of [3H]valproic acid and [14C]lactic acid was measured by using human placental brush-border membrane vesicles. Results. The uptakes of [3H]valproic acid and [14C]lactic acid into brush-border membrane vesicles were greatly stimulated at acidic extravesicular pH. The uptakes of [3H]valproic acid and [14C]lactic acid were inhibited by various fatty acids, p-chloromercuribenzene sulfonate, α-cyano-4-hydroxycinnamate, and FCCP. A kinetic analysis showed that it was saturable, with Michaelis constants (Kt) of 1.04 ± 0.41 mM and 1.71 ± 0.33 mM for [3H]valproic acid and [14C]lactic acid, respectively. Furthermore, lactic acid competitively inhibited [3H]valproic acid uptake and vice versa. Conclusion. These results suggest that the transport of valproic acid across the microvillous membrane of human placenta is mediated by a proton-linked transport system that also transports lactic acid. However, some inhibitors differentially inhibited the uptakes of [3H]valproic acid and [14C]lactic acid, suggesting that other transport systems may also contribute to the elevated fetal blood concentration of valproic acid in gravida.

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Ejects of Single and Repeated Treatment with Itraconazole on the Pharmacokinetics of Midazolam in Rats

Sawada Y., Takedomi S., Matsuo H., Ohtani H., Yamano K., Iga T.

Drug Metabolism and Pharmacokinetics (Drug Metabolism and Pharmacokinetics) 17 ( 4 ) 275 - 283 2002

ISSN 13474367

To estimate the influence of repeated administration of drug metabolism inhibitors on the extent of drug interaction, we investigated the ejects of single intravenous or repeated oral administration of itraconazole on the pharmacokinetics of midazolam in rats. In the single administration study, the plasma concentration of itraconazole was maintained by intravenous infusion, and midazolam was administered into the portal vein to investigate its kinetics. In the repeated administration study, the kinetics of midazolam was investigated after seven-day oral treatment with itraconazole. The in vitro metabolism of midazolam and the contents of cytochrome P450 were investigated using liver microsomes from the itraconazole-treated rats. © 2002, The Japanese Society for the Study of Xenobiotics. All rights reserved.

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Polymorphism of MDR1 Gene in Healthy Japanese Subjects: A Novel SNP with an Amino Acid Substitution (Glu108Lys)

Honda T., Dan Y., Koyabu N., Ohtani H., Sawada Y., Ieiri I., Otsubo K., Higuchi S.

Drug Metabolism and Pharmacokinetics (Drug Metabolism and Pharmacokinetics) 17 ( 5 ) 479 - 481 2002

ISSN 13474367

We discovered a novel single nucleotide polymorphism (SNP) at position 325 (G325A) in exon 5 of the multidrug-resistance 1 (MDR1) gene in a study of 37 healthy Japanese subjects. Details are as follows. SNP, 020614Honda001; GENE NAME, human P-glycoprotein (MDR1); ACCESSION NUMBER, M29427; LENGTH, 25 bases; 5' -ATGAATCTGGAGG/AAAGACATGACCA-3'. This SNP is expected to cause an amino acid substitution (Glu108Lys). In this study, one homozygote and one heterozygote for G325A were identified. © 2002, The Japanese Society for the Study of Xenobiotics. All rights reserved.

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H+-linked transport of salicylic acid, an NSAID, in the human trophoblast cell line BeWo

Emoto A., Ushigome F., Koyabu N., Kajiya H., Okabe K., Satoh S., Tsukimori K., Nakano H., Ohtani H., Sawada Y.

American Journal of Physiology - Cell Physiology (American Journal of Physiology - Cell Physiology) 282 ( 5 51-5 ) C1064 - 75 2002

ISSN 03636143

We investigated the transport of salicylic acid and L-lactic acid across the placenta using the human trophoblast cell line BeWo. We performed uptake experiments and measured the change in intracellular pH (pHi). The uptakes of [14C] salicylic acid and L-[14C] lactic acid were temperature- and extracellular pH-dependent and saturable at higher concentrations. Both uptakes were also reduced by FCCP, nigericin, and NaN3. Various nonsteroidal anti-inflammatory drugs (NSAIDs) strongly inhibited the uptake of L-[14C] lactic acid. Salicylic acid and ibuprofen noncompetitively inhibited the uptake of L-[14C] lactic acid. α-Cyano-4-hydroxycinnamate (CHC), a monocarboxylate transporter inhibitor, suppressed the uptake of L-[14C] lactic acid but not that of [14C] salicylic acid. CHC also suppressed the decrease of pHi induced by L-lactic acid but had little effect on that induced by salicylic acid or diclofenac. These results suggest that NSAIDs are potent inhibitors of lactate transporters, although they are transported mainly by a transport system distinct from that for L-lactic acid.

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Effects of grapefruit juice and orange juice on the intestinal efflux of P-glycoprotein substrates

Tian R., Koyabu N., Takanaga H., Matsuo H., Ohtani H., Sawada Y.

Pharmaceutical Research (Pharmaceutical Research) 19 ( 6 ) 802 - 809 2002

ISSN 07248741

Purpose. The aim of this study is to investigate the effects of 50% ethyl acetate extracts of grapefruit juice (GFJ) and orange juice (OJ) on the transport activity of P-glycoprotein (P-gp) in the rat small intestine. Methods. The efflux of P-gp substrates from rat everted sac in the absence or presence of verapamil, GFJ, OJ or erythromycin was measured. Rhodamine123, fexofenadine and saquinavir were used as P-gp substrates. P-gp expression levels in the rat jejunum and ileum were determined by Western blot analysis. Results. The efflux of rhodamine123 from the everted sac increased from the apex of the jejunum to the low ileum and the expression of P-gp in the ileum was 2.31-fold higher than that in the jejunum. Verapamil and the 50% GFJ and OJ extracts inhibited the efflux from the intestine of all three drugs tested. Erythromycin decreased the efflux of rhodamine123 and fexofenadine, but did not affect the efflux of saquinavir in the intestine. Conclusions. GFJ and OJ extracts inhibited the efflux of P-gp substrates from the small intestine. Therefore, they may enhance the oral bioavailability of P-gp substrates by increasing absorption in the small intestine.

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Transcellular transport of genistein, a soybean-derived Isoflavone, across human colon carcinoma cell line

Oitate M., Nakaki R., Koyabu N., Takanaga H., Matsuo H., Ohtani H., Sawada Y.

Biopharmaceutics and Drug Disposition (Biopharmaceutics and Drug Disposition) 22 ( 1 ) 23 - 29 2001.12

ISSN 01422782

Genistein, a soybean-derived isoflavone, is thought to have an anticarcinogenic action, but little is known about the cellular mechanisms of its intestinal absorption. This study was designed to investigate the absorption mechanisms of genistein using human colon carcinoma cell line, Caco-2 cells. The apical-to-basolateral transcellular transport of genistein across a Caco-2 cell monolayer was significantly greater than that in the opposite direction. An uptake experiment revealed that cellular uptake of genistein by Caco-2 cells was concentrative. The transcellular transport of genistein was saturable and temperature-dependent, and was inhibited by other flavonoids such as rutin, quercetin, (+)-catechin and (-)-epicatechin. These results suggest that genistein is transported across Caco-2 cells by a carrier-mediated system, located on the apical membrane. Copyright © 2001 John Wiley & Sons, Ltd.

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Quantitative relationship between myocardial concentration of tacrolimus and QT prolongation in guinea pigs: Pharmacokinetic/pharmacodynamic model incorporating a site of adverse effect

Minematsu T., Ohtani H., Yamada Y., Sawada Y., Sato H., Iga T.

Journal of Pharmacokinetics and Pharmacodynamics (Journal of Pharmacokinetics and Pharmacodynamics) 28 ( 6 ) 533 - 554 2001.12

ISSN 1567567X

Clinical cases have been reported of tacrolimus (FK506)-induced QT prolongation. We have previously demonstrated sustained QT prolongation by FK506 in guinea pigs. Herein, we aimed to conduct a pharmacokinetic/pharmacodynamic (PK/PD) analysis of FK506, using a model involving the myocardial compartment. The pharmacokinetics of FK506 and its effects on QTc intervals were investigated in guinea pigs. In the pharmacokinetic study, whole blood and ventricular FK506 concentrations were analyzed, using a 4-compartment model during and after intravenous infusion of FK506 (0.01 or 0.1 mg/hr/kg). Subsequently, the concentration-response relationship between ventricular FK506 concentration and change in QTc interval was analyzed, using the maximal effect (Emax) model. Pharmacokinetic profiles of FK506 showed a delayed distribution of FK506 into the ventricle. Furthermore, the observed QT prolongation paralleled the ventricular FK506 concentrations, with no lag-time between the two. The Emax model successfully described the relationship between changes in QTc interval and ventricular FK506 concentrations. In conclusion, the PK/PD model where the myocardial drug concentration of FK506 was linked with its adverse effect could describe, for the first time, the anti-clockwise hysteresis observed in the relationship between blood FK506 concentration and QT prolongation. Such a hysteresis pattern for QT prolongation might be caused, therefore, mainly by the delayed disposition of FK506 to ventricular myocytes.

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Pharmacokinetic and pharmacodynamic analysis of the antihypercalcemic effect of incadronate disodium in rats

Ohno Y., Yamada Y., Usui T., Takahashi K., Tsuchiya F., Ohtani H., Sato H., Sawada Y., Iga T.

Biological and Pharmaceutical Bulletin (Biological and Pharmaceutical Bulletin) 24 ( 11 ) 1290 - 1293 2001.11

ISSN 09186158

Incadronate concentrates into the bone as a target organ after intravenous administration of incadronate disodium. Mature osteoclasts has take up incadronate from the bone surface and convert it from an active to an inactive form. As a result, incadronate decreases the plasma calcium concentration by suppressing bone resorption. In this study, the pharmacokinetic and pharmacodynamic (PK/PD) analysis model for ascertaining the anti-hypercalcemic effects of incadronate disodium was developed in rats. Data on both the concentration of incadronate in bone and that of free calcium in blood after intravenous administration from our previous study were used for analysis. To estimate the concentration in the surface layer of bone, data on the concentration of incadronate in bone after single intravenous administration were analyzed based on the PK model considering three-compartments. The estimated concentrations in the surface layer in bone were applied to the PD model as an input function. The PD model was developed to analyze the changes in the plasma calcium concentration after a single intravenous administration considering an irreversible inhibition of osteoclast activity. The obtained fitted curves were in good agreement with the observed data. The model could explain the long duration of the antihypercalcemic effect of incadronate disodium and should be useful for planning rational dose regimens for effective antihypercalcemic therapy.

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Possibility of the reversal of multidrug resistance and the avoidance of side effects by liposomes modified with MRK-16, a monoclonal antibody to P-glycoprotein

Matsuo H., Wakasugi M., Takanaga H., Ohtani H., Naito M., Tsuruo T., Sawada Y.

Journal of Controlled Release (Journal of Controlled Release) 77 ( 1-2 ) 77 - 86 2001.11

ISSN 01683659

For cancer chemotherapy, avoiding the side effects of chemotherapeutic agents is difficult. Multidrug resistance is one of the major obstacles to successful cancer chemotherapy. P-Glycoprotein (P-gp) serves as an efflux pump and plays a key role in the multidrug resistance. We examined the effect of MRK-16, a monoclonal antibody against P-gp, modified liposomes (MRK-Lip) on the human myelogenous leukemia K-562 cells and its adriamycin resistance cell line K-562/ADM cells to avoid the side effects and to reverse the multidrug resistance. The uptake of vincristine (VCR) by K-562/ADM cells was lower than that by K-562 cells. This low uptake was increased in the presence of verapamil and MRK-16, however, it was not increased in the presence of control antibody, IgG2A. The binding of MRK-Lip to K-562/ADM cells was higher than that of IgG2A-modified liposome (IgG-Lip) and liposome without modification (Cont-Lip). Moreover, the cytotoxicity of VCR-encapsulated MRK-Lip to K-562/ADM cells was higher than that of VCR-encapsulated IgG-Lip and Cont-Lip. These results suggest that the interaction between liposomes and multidrug resistance cells was increased by the modification of liposomes with MRK-16. Consequently, the usefulness of MRK-Lip in cancer chemotherapy as a potent carrier was suggested. © 2001 Elsevier Science B.V. All rights reserved.

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Pharmacokinetics and drug interactions of antidepressive agents

Sawada Y., Ohtani H.

Nippon rinsho. Japanese journal of clinical medicine (Nippon rinsho. Japanese journal of clinical medicine) 59 ( 8 ) 1539 - 1545 2001.08

ISSN 00471852

Tricyclic antidepressive agents(TCAs) are conventional antidepressant. Cytochrome P450(CYP) 2D6 is involved in the hydroxylation of TCAs, while N-demethylation of TCAs is mediated by other such as CYP2C19, 3A4 and 1A2. The elimination of TCAs is impaired by CYP2D6 inhibitors such as quinidine. Newer antidepressants, selective serotonin uptake inhibitors(SSRIs), are also metabolized in the liver. Fluvoxamine, an SSRI, is a potent inhibitors for CYP1A2 and CYP2C19, moderate for CYP3A4 and weak for CYP 2D6. Paroxetine, another SSRI, causes substantial inhibition of CYP2D6 activity. Milnacipran, a serotonin and noradrenaline reuptake inhibitor, is mainly excreted unchanged in urine and some part as its glucronide conjugate. In contrast to many SSRIs, milnacipran is devoid of metabolic inhibition.

[Pharmacokinetics and drug interactions of antidepressive agents].

Sawada Y, Ohtani H

Nihon rinsho. Japanese journal of clinical medicine 59 ( 8 ) 1539 - 45 2001.08

ISSN 0047-1852

A comparative pharmacodynamic study of the arrhythmogenicity of antidepressants, fluvoxamine and imipramine, in guinea pigs

Ohtani H., Odagiri Y., Sato H., Sawada Y., Iga T.

Biological and Pharmaceutical Bulletin (Biological and Pharmaceutical Bulletin) 24 ( 5 ) 550 - 554 2001.06

ISSN 09186158

Among several classes of antidepressants, tricyclic antidepressants are known to prolong QTc intervals (QT interval corrected by heart rate) in electrocardiograms, while selective serotonin uptake inhibitors (SSRI) are considered to be devoid of arrhythmogenicity. In this study, we aimed to compare the arrhythmogenic potencies of imipramine (IMI), a typical tricyclic antidepressant, and fluvoxamine (FLV), an SSRI, at therapeutic and supratherapeutic concentrations using guinea pigs in vivo. Guinea pigs were anesthetized, and IMI (10 and 20 mg/kg/h) or FLV (20 mg/kg/h) was intravenously administered for 90 minutes to obtain the time-courses of drug concentrations in plasma and the changes in the QTc intervals during and after the drug administration. IMI induced distinct QTc prolongation in a dose-dependent manner, while FLV prolonged QTc intervals only slightly. A pharmacokinetic-pharmacodynamic analysis revealed that the potency for QTc prolongation of IMI was 1.7-fold higher than that of FLV. Taking the therapeutic concentration into account, the clinical risk of FLV for QTc prolongation was suggested to be 5-fold lower than that of IMI. Therefore, this SSRI agent was suggested to be safer than the tricyclic antidepressant for patients with cardiac risk factors, including arrhythmia, or for those taking other arrhythmogenic drugs concomitantly.

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In-vivo kinetics of the interaction between midazolam and erythromycin in rats, taking account of metabolic intermediate complex formation

Takedomi S., Matsuo H., Yamano K., Ohtani H., Sawada Y.

Journal of Pharmacy and Pharmacology (Journal of Pharmacy and Pharmacology) 53 ( 5 ) 643 - 651 2001.05

ISSN 00223573

To predict, quantitatively, the extent of drug interaction during repeated administration of a metabolic inhibitor, we analysed the effects of erythromycin treatment under several regimens on the area under the concentration curve (AUC) of midazolam in rats. Midazolam was administered into the portal vein 12 h after erythromycin treatment for 1, 2 or 3 days, or 12, 24, 36, 48, 72 and 96 h after erythromycin treatment for 4 days, and the plasma-concentration profiles of midazolam were analysed to assess the AUC. Moreover, the contents of total cytochrome P450 and inactive metabolic intermediate (MI) complex were simultaneously quantitated. While the AUC value of midazolam was not affected by the administration of erythromycin for 1 day, repeated administration of erythromycin evoked an increase in AUC ratio (AUC in erythromycin-treated rats/AUC in vehicle-treated rats), which reached a maximum value of 1.99 at 12 h after 4 days' treatment with erythromycin. The total content of cytochrome P450 in liver microsomes was unaffected by erythromycin treatment. Although the MI complex was undetectable after 1 day's treatment with erythromycin, its content increased with duration of erythromycin treatment, and the complex disappeared after the end of erythromycin treatment with a half-life of 12.3 h. In conclusion, the interaction between erythromycin and midazolam could be well predicted when the formation of MI complex in the liver was taken into account.

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Prediction of midazolam - CYP3A inhibitors interaction in the human liver from in vivo/in vitro absorption, distribution, and metabolism data

Yamano K., Yamamoto K., Katashima M., Kotaki H., Takedomi S., Matsuo H., Ohtani H., Sawada Y., Iga T.

Drug Metabolism and Disposition (Drug Metabolism and Disposition) 29 ( 4 I ) 443 - 452 2001.04

ISSN 00909556

The extent of decreases in apparent hepatic clearance and intrinsic hepatic clearance of midazolam (MDZ) after intravenous administration of MDZ with concomitant oral administration of cimetidine (CIM), itraconazole (ITZ), or erythromycin (EM) was predicted using plasma unbound concentrations and liver unbound concentrations of inhibitors. When MDZ was concomitantly administered with CIM, the observed increase in MDZ concentration was successfully predicted using inhibition constants assessed by human liver microsome and liver-to-plasma unbound concentration ratios in rats. However, the extent of interaction with ITZ or EM was still underestimated even taking into account the concentrative uptake of inhibitors into liver. We could predict the degree of "mechanism-based" inhibition by EM on the hepatic metabolism of MDZ, after repeated administration of EM, by a physiological model incorporating the amount of active enzyme as well as the concentration of inhibitor. The maximum inactivation rate constant and the apparent inactivation constant of EM on MDZ metabolism were 0.0665 min-1 and 81.8 μM, respectively. These kinetic parameters for the inactivation of the enzyme were applied to the physiological model with pharmacokinetic parameters of EM and MDZ obtained from published results. Consequently, we estimated that cytochrome P450 3A4 in the liver after repeated oral administration of EM was inactivated, resulting in 2.6-fold increase in the plasma concentration of MDZ. The estimated extent of increase in MDZ concentration in our study correlated well with the observed value based on metabolic inhibition by EM from published results.

Uptake mechanism of valproic acid in human placental choriocarcinoma cell line (BeWo)

Ushigome F., Takanaga H., Matsuo H., Tsukimori K., Nakano H., Ohtani H., Sawada Y.

European Journal of Pharmacology (European Journal of Pharmacology) 417 ( 3 ) 169 - 176 2001.04

ISSN 00142999

Valproic acid is an anticonvulsant widely used for the treatment of epilepsy. However, valproic acid is known to show fetal toxicity, including teratogenicity. In the present study, to elucidate the mechanisms of valproic acid transport across the blood-placental barrier, we carried out transcellular transport and uptake experiments with human placental choriocarcinoma epithelial cells (BeWo cells) in culture. The permeability coefficient of [3H]valproic acid in BeWo cells for the apical-to-basolateral flux was greater than that for the opposite flux, suggesting a higher unidirectional transport in the fetal direction. The uptake of [3H]valproic acid from the apical side was temperature-dependent and enhanced under acidic pH. In the presence of 50 μM carbonyl cyanide p-trifluoromethoxylhydrazone, the uptake of [3H]valproic acid was significantly reduced. A metabolic inhibitor, 10 mM sodium azide, also significantly reduced the uptake of [3H]valproic acid. Therefore, valproic acid is actively transported in a pH-dependent manner on the brush-border membrane of BeWo cells. Kinetic analysis of valproic acid uptake revealed the involvement of a non-saturable component and a saturable component. The Michaelis constant for the saturable transport (Kt) was smaller under acidic pH, suggesting a proton-linked active transport mechanism for valproic acid in BeWo cells. In the inhibitory experiments, some short-chain fatty acids, such as acetic acid, lactic acid, propanoic acid and butyric acid, and medium-chain fatty acids, such as hexanoic acid and octanoic acid, inhibited the uptake of [3H]valproic acid. The uptake of [3H]valproic acid was also significantly decreased in the presence of 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid, salicylic acid and furosemide, which are well-known inhibitors of the anion exchange system. Moreover, p-aminohippuric acid significantly reduced the uptake of [3H]valproic acid. These results suggest that an active transport mechanism for valproic acid exists on the brush-border membrane of placental trophoblast cells and operates in a proton-linked manner. © 2001 Published by Elsevier Science B.V.

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Assessment of systemic adverse reactions induced by ophthalmic β-adrenergic receptor antagonists

Yamada Y., Takayanagi R., Tsuchiya K., Ito K., Ohtani H., Sawada Y., Iga T.

Journal of Ocular Pharmacology and Therapeutics (Journal of Ocular Pharmacology and Therapeutics) 17 ( 3 ) 235 - 248 2001

ISSN 10807683

To assess quantitatively the risks of ophthalmic beta-blocking agents for cardiovascular and respiratory adverse reactions, we analyzed the binding kinetics of beta-blocking agents to the beta-1 and beta-2 adrenoceptors. The relationship between the occupancies for beta-1 and beta-2 adrenoceptors and the effects on the exercise pulse rate or the forced expiratory volume in one second (FEV1) after topical administration of carteolol, befunolol, timolol and betaxolol was analyzed using a ternary complex model. The beta-1 and beta-2 receptor occupancies after ophthalmic administration were calculated to be quite high as well as those after oral administration. The maximum occupancies for beta-1 and beta-2 receptors after ordinary ophthalmic administration were 52% and 88% for carteolol, 52% and 61% for befunolol, 62% and 82% for timolol, and 44% and 3% for betaxolol, respectively. Concave relationships were obtained between a decrease in exercise pulse rate and the beta-1 receptor occupancy and between a decrease in FEV1 and beta-2 receptor occupancy, respectively. Nasolacrimal occlusion was estimated to decrease the exercise pulse rate and FEV1 by 65% and 50%, respectively. The beta-1 and beta-2 adrenoceptor occupancies were proved to be the most appropriate indicators for cardiac and pulmonary adverse reactions evoked by ophthalmic beta-blocking agents.

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Characteristics of choline transport across the blood-brain barrier in mice: Correlation with in vitro data

Murakami H., Sawada N., Koyabu N., Ohtani H., Sawada Y.

Pharmaceutical Research (Pharmaceutical Research) 17 ( 12 ) 1526 - 1530 2000.12

ISSN 07248741

Purpose. We examined the functional properties of choline transport across the blood-brain barrier (BBB) in mice. We compared the kinetic parameters and transport properties with those found in our in vitro uptake experiments using mouse brain capillary endothelial cells (MBEC4). Methods. The permeability coefficient-surface area product (PS) values of [3H]choline at the BBB were estimated by means of an in situ brain perfusion technique in mice. Results. [3H]Choline uptake was well described by a two-component model: a saturable component and a nonsaturable linear component. The [3H]choline uptake was independent of pH and Na+, but was significantly decreased by the replacement of Na+ with K+. Various basic drugs, including substrates and inhibitors of the organic cation transporter, significantly inhibited the [3H]choline uptake. These in situ (in vivo) results corresponded well to the in vitro results and suggest that the choline transporter at the BBB is a member of the organic cation transporter (OCT) family. Conclusion. The choline transport mechanism at the BBB is retained in MBEC4.

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Quantitative prediction of catalepsy induced by amoxapine, cinnarizine and cyclophosphamide in mice

Nasu R., Matsuo H., Takanaga H., Ohtani H., Sawada Y.

Biopharmaceutics and Drug Disposition (Biopharmaceutics and Drug Disposition) 21 ( 4 ) 129 - 138 2000.12

ISSN 01422782

Parkinsonism can be a side effect of antipsychotic drugs, and has recently been reported with peripherally acting drugs such as calcium channel blockers, antiarrhythmic agents and so on. In this study, we examined the quantitative prediction of drug-induced catalepsy by amoxapine, cinnarizine and cyclophosphamide, which have been reported to induce parkinsonism. Dose-dependent catalepsy was induced by these drugs in mice. In vivo dopamine D1, D2 and muscarinic acetylcholine (mACh) receptor occupancies by these drugs in the striatum were also examined. The in vitro binding affinities (Ki values) of amoxapine and cinnarizine to dopamine D1, D2 and mACh receptors in rat striatal synaptic membrane were 200 and 2900 nM, 58.4 and 76.4 nM and 379 and 290 nM, respectively. Cyclophosphamide did not bind to these receptors at concentrations up to 100 μM. Twenty drugs, including those mentioned above, showed a significant correlation between the observed intensity of catalepsy and the values predicted with a pharmacodynamic model (Haraguchi K, Ito K, Kotaki H, Sawada Y, Iga T. Prediction of drug-induced catalepsy based on dopamine D1, D2, and muscarinic acetylcholine receptor occupancies. Drug Metab Disp 1997; 25: 675-684) based on in vivo occupancy of dopamine D1, D2 and mACh receptors. We conclude that occupancy of dopamine D1 and D2 receptors contributes to catalepsy induction by amoxapine and cinnarizine. Copyright © 2000 John Wiley & Sons, Ltd.

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Human placental transport of vinblastine, vincristine, digoxin and progesterone: Contribution of P-glycoprotein

Ushigome F., Takanaga H., Matsuo H., Yanai S., Tsukimori K., Nakano H., Uchiumi T., Nakamura T., Kuwano M., Ohtani H., Sawada Y.

European Journal of Pharmacology (European Journal of Pharmacology) 408 ( 1 ) 1 - 10 2000.11

ISSN 00142999

To elucidate the role of P-glycoprotein in human placenta, we examined its expression in placenta, and the transcellular transport and uptake of P-glycoprotein substrates in cultured human placental choriocarcinoma epithelial cells (BeWo cells). The uptake of [3H]vinblastine and [3H]vincristine into BeWo cells was increased in the presence of a metabolic inhibitor, sodium azide. The basolateral-to-apical transcellular transport of [3H]vinblastine, [3H]vincristine and [3H]digoxin was greater than the apical-to-basolateral transcellular transport. In the presence of cyclosporin A, the basolateral-to-apical transcellular transport of [3H]vinblastine, [3H]vincristine and [3H]digoxin was significantly increased, and the apical-to-basolateral transcellular transport was decreased. The uptake of [3H]vinblastine, [3H]vincristine and [3H]digoxin into BeWo cells was significantly enhanced in the presence of several inhibitors, such as verapamil or mouse monoclonal antibody anti-P-glycoprotein MX-MDR (MRK16) as well as cyclosporin A. Although progesterone significantly enhanced the uptake of [3H]vinblastine, [3H]vincristine and [3H]digoxin into BeWo cells, the uptake of [3H]progesterone was not affected by these inhibitors. Immunoblot analysis revealed that P-glycoprotein with a molecular weight of 172 kDa was expressed in BeWo cells and isolated trophoblast cells. Furthermore, P-glycoprotein was detected in human placental brush-border membrane vesicles, but not in human placental basolateral membrane vesicles. In conclusion, these data suggest that P-glycoprotein is expressed on the brush-border membrane (maternal side) of human placental trophoblast cells. P-Glycoprotein is considered to regulate the transfer of several substances including vinblastine, vincristine and digoxin from mother to fetus, and to protect the fetus from toxic substances. (C) 2000 Elsevier Science B.V.

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Inhibition of P-glycoprotein by orange juice components, polymethoxyflavones in adriamycin-resistant human myelogenous leukemia (K562/ADM) cells

Ikegawa T., Ushigome F., Koyabu N., Morimoto S., Shoyama Y., Naito M., Tsuruo T., Ohtani H., Sawada Y.

Cancer Letters (Cancer Letters) 160 ( 1 ) 21 - 28 2000.11

ISSN 03043835

We investigated the effects of the ethyl acetate extract of grapefruit juice (GFJ), that of orange juice (OJ) and their components on the uptake of [3H]vincristine into adriamycin-resistant human myelogenous leukemia cells. Its uptake was increased by the extracts of GFJ and OJ up to 7- and 3-fold, respectively, as well as verapamil and cyclosporin A. OJ components, i.e. 3,3',4',5,6,7,8-heptamethoxyflavone, nobiletin and tangeretin, also increased the uptake of [3H]vincristine in a concentration-dependent manner. Although GFJ components, dihydroxybergamottin and bergamottin, significantly increased the uptake, their potencies were considerably weaker than those of OJ components. These data suggest that OJ components inhibit P-gp-mediated efflux of [3H]vincristine, resulting in the intracellular accumulation of chemotherapeutic drugs. These components may become candidates of multi-drug resistance reversing agents in cancer chemotherapy. Copyright (C) 2000 Elsevier Science Ireland Ltd.

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Propiverine-induced Parkinsonism: A case report and a pharmacokinetic/pharmacodynamic study in mice

Matsuo H., Matsui A., Nasu R., Takanaga H., Inoue N., Hattori F., Ohtani H., Sawada Y.

Pharmaceutical Research (Pharmaceutical Research) 17 ( 5 ) 565 - 571 2000.07

ISSN 07248741

Purpose. We present a case report of propiverine-induced Parkinsonism. We previously reported the induction of catalepsy by amiodarone, aprindine and procaine, which possess a diethylaminomethyl moiety and demonstrated selective blockade of dopamine D2 receptors by these drugs in mice. We hypothesized that drugs possessing a diethylaminomethyl structure may generally induce Parkinsonism and/or catalepsy. Methods. Thus, we performed a study to examine whether oxybutynin, pentoxyverine and etafenone, as well as propiverine, induce catalepsy in mice. Results. The intensity of drug-induced catalepsy was in the order: haloperidol > etafenone > pentoxyverine > propiverine > oxybutynin. In vivo occupancy of dopamine D1, D2 and mACh receptors in the striatum was also examined. The in vitro binding affinities to the D1, D2 and mACh receptors in the striatum synaptic membrane were within the ranges of 2.4-140 μM, 380-4,200 nM, and 1.2-2,800 nM, respectively. Conclusions. These results support the idea that any drug possessing a diethylaminomethyl moiety may contribute to the induction of catalepsy, possibly by occupying dopamine receptors.

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Effect of bioflavonoids on vincristine transport across blood-brain barrier

Mitsunaga Y., Takanaga H., Matsuo H., Naito M., Tsuruo T., Ohtani H., Sawada Y.

European Journal of Pharmacology (European Journal of Pharmacology) 395 ( 3 ) 193 - 201 2000.05

ISSN 00142999

Several grapefruit juice bioflavonoids, including quercetin, are reported to stimulate P-glycoprotein-mediated drug efflux from cultured tumor cells. To see whether these bioflavonoids alter the permeation of vincristine across the blood-brain barrier, we conducted experiments with cultured mouse brain capillary endothelial cells (MBEC4 cells) in vitro and ddY mice in vivo. The steady-state uptake of [3H]vincristine by MBEC4 cells was decreased by 10 μM quercetin, but increased by 50 μM quercetin. Similarly, the in vivo brain-to-plasma concentration ratio of [3H]vincristine in ddY mice was decreased by coadministration of 0.1 mg/kg quercetin, but increased by 1.0 mg/kg quercetin. Kaempferol had a similar biphasic effect on the in vitro uptake of [3H]vincristine. Other aglycones tested (chrysin, flavon, hesperetin, naringenin) increased [3H]vincristine uptake in the 10-50 μM range, and glycosides (hesperidin, naringin, rutin) were without effect. We then addressed the mechanism of the concentration-dependent biphasic action of quercetin. Verapamil, a P-glycoprotein inhibitor, inhibited the efflux of [3H]vincristine from MBEC4 cells, while 10 μM quercetin significantly stimulated it. The uptake of [3H]vincristine by MBEC4 cells was increased by inhibitors of protein kinase C, but decreased by phorbol 12-myristate-13- acetate (PMA), as well as by 10 μM quercetin. The phosphorylation level of P-glycoprotein was increased in the presence of 5 μM quercetin or 100 nM PMA, but decreased by the protein kinase C inhibitor H7 (1-(5- isoquinolinesulfonyl)-2-methylpiperazine, 30 μM). We conclude that low concentrations of quercetin indirectly activate the transport of [3H]vincristine by enhancing the phosphorylation (and hence activity) of P- glycoprotein, whereas high concentrations of quercetin inhibit P- glycoprotein. Our results indicate that patients taking drugs which are P- glycoprotein substrates may need to restrict their intake of bioflavonoid- containing foods and beverages, such as grapefruit juice. (C) 2000 Elsevier Science B.V.

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Induction of apoptosis in mouse brain capillary endothelial cells by cyclosporin A and tacrolimus

Kochi S., Takanaga H., Matsuo H., Ohtani H., Naito M., Tsuruo T., Sawada Y.

Life Sciences (Life Sciences) 66 ( 23 ) 2255 - 2260 2000.04

ISSN 00243205

Although cyclosporin A and tacrolimus are used clinically as potent immunosuppressants, there have been reports of neurotoxicity and encephalopathy. A possible mechanism is that these drugs damage the blood- brain barrier (BBB), inducing dysfunction and increased permeability, and are then able to enter the brain. We studied the cytotoxicity of cyclosporin A and tacrolimus, focused on apoptosis induction, using an immortalized cell line established from BALB/c mouse cerebral microvessel endothelial cells (MBEC4). We found that these two drugs induced cell shrinkage, chromatin condensation and DNA fragmentation, which are characteristics of apoptosis. Our data suggest that the induction of apoptosis on the brain capillary endothelial cells may be at least partly involved in the occurrence of immunosuppressant-induced encephalopathy.

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Polymethoxylated flavones in orange juice are inhibitors of P- glycoprotein but not cytochrome P450 3A4

Takanaga H., Ohnishi A., Yamada S., Matsuo H., Morimoto S., Shoyama Y., Ohtani H., Sawada Y.

Journal of Pharmacology and Experimental Therapeutics (Journal of Pharmacology and Experimental Therapeutics) 293 ( 1 ) 230 - 236 2000.04

ISSN 00223565

The presence in orange juice of compounds that specifically inhibit the P-glycoprotein (P-gp) drug efflux transporter, but not the cytochrome P450 (CYP) isozyme CYP3A4, was investigated. The uptake of [3H]vinblastine, a substrate of P-gp, by Caco-2 cells was measured. An ethyl acetate extract of orange juice did not affect the initial uptake rate of [3H]vinblastine but significantly increased the steady-state uptake, as did cyclosporin A (20 μM), an inhibitor of P-gp. No significant effect on the uptake of 3-O- [3H]methylglucose or [14C]phenylalanine by Caco-2 cells was found, compared with the control. When the extract was separated on a Cosmosil column, the eluate with 70% methanol showed the most potent ability to increase [3H]vinblastine uptake. Additional separation of the 70% methanol eluate on a silica gel column with hexane-acetone (3:1) gave 3,3',4',5,6,7,8- heptamethoxyflavone (HMF) and 4',5,6,7,8-pentamethoxyflavone (tangeretin). HMF, tangeretin, and 3',4',5,6,7,8-hexamethoxyflavone (nobiletin), another methoxyflavone contained in orange juice, all increased the steady-state uptake of [3H]vinblastine by Caco-2 cells in a concentration-dependent manner. The order of potency of these compounds at the concentration of 50 μM was tangeretin > HMF > nobiletin. None of these methoxyflavones inhibited 6β-hydroxylation of testosterone catalyzed by CYP3A4. The ethyl acetate extract of orange juice and these methoxyflavones also increased steady-state [3H]vinblastine uptake by LLC-GA5-COL300 cells (a cell line transfected with human MDR1 cDNA). We conclude that these methoxyflavones enhanced vinblastine uptake by specifically inhibiting drug efflux via P-gp. They may have potential as agents for reversing multidrug resistance or for recovering the bioavailability of certain drugs.

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Determination of erythromycin, clarithromycin, roxithromycin, and azithromycin in plasma by high-performance liquid chromatography with amperometric detection

Taninaka C., Ohtani H., Hanada E., Kotaki H., Sato H., Iga T.

Journal of Chromatography B: Biomedical Sciences and Applications (Journal of Chromatography B: Biomedical Sciences and Applications) 738 ( 2 ) 405 - 411 2000.02

ISSN 13872273

In this study, a high-performance liquid chromatographic method was developed for the quantitative determination of erythromycin (EM), roxithromycin (RXM), and azithromycin (AZM) in rat plasma with amperometric detection under a standardized common condition using clarithromycin (CAM) as an internal standard. This method was also proved to be applicable for the determination of CAM by employing RXM as an internal standard. Each drug was extracted from 150 μl of plasma sample spiked with internal standard under an alkaline condition with tert.-butyl methyl ether. The detector cell potential for the oxidation of the drugs was set at +950 mV. The linearity of the calibration curves were preserved over the concentration ranges of 0.1-10 μg/ml for EM and RXM, and 0.03-3.0 μg/ml for CAM and AZM. Coefficients of variation and relative error were less than 9% and ±7%, respectively. The analytical method presented here was proved to be useful for the investigation of the pharmacokinetic characteristics of EM, CAM, RXM, and AZM in rats. (C) 2000 Elsevier Science B.V.

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Influence of extracellular K+ concentrations on quinidine-induced K+ current inhibition in rat ventricular myocytes

Hirota M., Ohtani H., Hanada E., Sato H., Kotaki H., Uemura H., Nakaya H., Tatsuji I.

Journal of Pharmacy and Pharmacology (Journal of Pharmacy and Pharmacology) 52 ( 1 ) 99 - 105 2000.01

ISSN 00223573

Hypokalaemia is one of the important risk factors for development of torsades de pointes. We recently reported that hypokalaemia increased the electrocardiographic QT interval in rats treated with quinidine, but did not alter the arrhythmogenic potency of quinidine. In this study, we have investigated the influence of extracellular potassium concentration ([K+](o)) on the inhibition of several types of cardiac potassium currents by quinidine. Such types of currents include the delayed rectifier potassium current (I(K)), the transient outward current (I(to)), and the inward rectifier potassium current (I(K1)), as measured in isolated rat ventricular cells using patch-clamp techniques. Concentration-dependent effects of quinidine on I(K), I(to), and I(K1) were evaluated under both normal ([K+](o) = 5.4 mM) and hypokalaemic ([K+](o) = 3.5 mM) conditions. In contrast to both I(K) and I(to), which were barely influenced by changes in [K+](o), I(K1) was significantly inhibited by hypokalaemia. Furthermore, while quinidine suppressed both I(K) and I(to) in a concentration-dependent manner, the inhibitory potency of quinidine on these currents was not influenced by changes in [K+](o). The respective normal and hypokalaemic IC50 values for quinidine were 11.4 and 10.0 μM (I(K)), and 17.6 and 17.3 μM (I(to)). Although higher concentrations of quinidine were required to inhibit I(K1), the inhibitory potency of quinidine was also found to be insensitive to changes in [K+](o). Thus, in rats, the inhibitory potency of quinidine for the K+ current-types I(K), I(to) and I(K1) is barely influenced by changes in [K+](o). These findings are consistent with our previous report showing that the QT-prolonging potency of quinidine was not altered under hypokalaemic conditions. However, whilst hypokalemia does not affect I(K) or I(to), it can inhibit I(K1) and can result in QT prolongation in-vivo.

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Comparative pharmacodynamic analysis of Q-T interval prolongation induced by the macrolides clarithromycin, roxithromycin, and azithromycin in rats

Ohtani H., Taninaka C., Hanada E., Kotaki H., Sato H., Sawada Y., Iga T.

Antimicrobial Agents and Chemotherapy (Antimicrobial Agents and Chemotherapy) 44 ( 10 ) 2630 - 2637 2000

ISSN 00664804

In order to evaluate the arrhythmogenic potency of macrolide antibiotics in a quantitative manner, we analyzed the influence of clarithromycin (CAM), roxithromycin (RXM), and azithromycin (AZM) on Q-T intervals from pharmacokinetic and pharmacodynamic points of view and in comparison with the potency of erythromycin (EM) previously reported by us for rats. Male Sprague-Dawley rats were anesthetized, and CAM (6.6, 21.6, and 43.2 mg/kg of body weight/h), RXM (20 and 40 mg/kg/h), and AZM (40 and 100 mg/kg/h) were intravenously injected for 90 min to obtain the time courses of drag concentrations in plasma and the changes in the Q-T intervals during and after the drug injections. Distinct Q-T interval prolongation of up to 10 ms was observed with CAM at its clinical concentrations. RXM and AZM evoked Q-T interval prolongation at concentrations higher than their clinical ranges. The potencies for Q-T interval prolongation, assessed as the slope of the concentration-response relationship, were 6.09, 0.536, and 0.989 ms · ml/μg for CAM, RXM, and AZM, respectively. There was hysteresis between the change in the Q-T intervals and the time course of the plasma concentration of each drug. The rank order of clinical arrhythmogenicity was estimated to be EM > CAM > RXM > AZM, as assessed from the present results and our previous report for EM. In conclusion, RXM and AZM were estimated to be less potent at provoking arrhythmia than EM and CAM. These results should be useful for malting a safer choice of an appropriate agent for patients with electrocardiographic risk factors.

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Effect of furanocoumarin derivatives in grapefruit juice on the uptake of vinblastine by Caco-2 cells and on the activity of cytochrome P450 3A4

Ohnishi A., Matsuo H., Yamada S., Takanaga H., Morimoto S., Shoyama Y., Ohtani H., Sawada Y.

British Journal of Pharmacology (British Journal of Pharmacology) 130 ( 6 ) 1369 - 1377 2000

ISSN 00071188

1. The presence of inhibitors of drug efflux transporters, such as P-glycoprotein (P-gp), in grapefruit juice (GFJ) was confirmed based on the uptake of [3H]-vinblastine (VBL) by Caco-2 cells. 2. The uptake of [3H]-VBL by Caco-2 cells was significantly increased by the ethyl acetate extract of GFJ as well as by cyclosporin A. The extract was separated on a Cosmosil column and the eluate with 60% methanol increased [3H]-VBL uptake, while the activity to inhibit CYP3A4 was greatest in the 70 and 80% eluates. 3. These results show that the major inhibitor of efflux transport of VBL is different from that of CYP3A4. 4. Further separation of the 60% methanol eluate afforded dihydroxybergamottin (DHBG). Both ethyl acetate extract of GFJ and DHBG increased steady-state [3H]-VBL uptake by LLC-GA5-COL300 cells. Besides DHBG, other furanocoumarins contained in GFJ, such as bergamottin, FC726, bergaptol and bergapten, increased the steady-state uptake of [3H]-VBL by Caco-2 cells. 5. The order of inhibitory potency of these compounds was FC726 > DHBG > bergamottin > bergapten > bergaptol. While, the IC50 values for inhibition of CYP3A4 were 0.075, 0.45, 1.0, 1.0 and > 20 μM, respectively. Bergaptol specifically inhibited VBL efflux. 6. DHBG was thus identified as a candidate for inhibitors of VBL transport, together with other furanocoumarins. Moreover, partly involvement of the P-gp inhibition was suggested. 7. Therefore, the inhibition of efflux transport of drugs as well as of drug metabolism by CYP3A4 could be an important cause of drug-GFJ interaction.

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Comparison of blood-brain barrier permeability in mice and rats using in situ brain perfusion technique

Murakami H., Takanaga H., Matsuo H., Ohtani H., Sawada Y.

American Journal of Physiology - Heart and Circulatory Physiology (American Journal of Physiology - Heart and Circulatory Physiology) 279 ( 3 48-3 ) H1022 - 8 2000

ISSN 03636135

Here we present a method for measuring the permeability coefficient-surface area product (PS) values at the blood-brain barrier in mice, using the in situ brain perfusion technique originally developed for rats by Takasato et al. (Am J Physiol Heart Circ Physiol 247: H484-H493, 1984). Retrograde infusion into the right external carotid artery increased the carotid perfusion pressure in proportion to the perfusion rate. Intravascular volume and cerebral perfusion fluid flow at a perfusion rate of 1.0 ml/min in mice were similar to those in rats. In addition, the contribution of systemic blood to total flow in the hemisphere was small (only 3.2%). These findings indicated that this perfusion rate is suitable for mice. The PS values of more than 20 different compounds were determined in mice by using the in situ brain perfusion technique, and comparisons were made with data from rats. There was a close relationship (1:1) between the PS values in mice and rats, indicating that brain capillary permeabilities are similar in mice and rats.

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Efficient introduction of macromolecules and oligonucleotides into brain capillary endothelial cells using HVJ-liposomes.

Matsuo H, Okamura T, Chen J, Takanaga H, Ohtani H, Kaneda Y, Naito M, Tsuruo T, Sawada Y

Journal of drug targeting 8 ( 4 ) 207 - 16 2000

ISSN 1061-186X

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Pharmacokinetic/pharmacodynamic analysis of tacrolimus-induced QT prolongation in guinea pigs

Minematsu T., Ohtani H., Sato H., Iga T.

Biological and Pharmaceutical Bulletin (Biological and Pharmaceutical Bulletin) 22 ( 12 ) 1341 - 1346 1999.12

ISSN 09186158

Recently, several reports of clinical cases of QT prolongation and torsades de pointes, associated with the use of tacrolimus (FK506), have come to light. We have previously demonstrated FK506-induced QT prolongation in guinea pigs [Minematsu T., et al., Life Sci., 65, PL197-PL202 (1999)]. We now examined the relationship between QTc prolongation and the pharmacokinetics of FK506 in guinea pigs, in order to evaluate the arrhythmogenicity of FK506 when compared with that of quinidine sulfate (QND). Thus, dose-response relationships for FK506 (0.01 or 0.1 mg/h/kg) or QND (30 mg/h/kg) were investigated during and after intravenous infusion and also following intravenous bolus administration of FK506 (0.2 mg/kg). The dose-response relationship between plasma drug concentration and QTc prolongation for FK506 and QND were subsequently analyzed using an effect compartment model. The pharmacodynamic parameters thus obtained were as follows: k(E0) 2.72 X 10-4 (min-1), E(max) 27.1 (ms), EC50 0.376 (ng/ml) for FK506; and k(E0) 0.148 (min-1), K 8.41 (ms · ml/μg) for QND. The anti-clockwise hysteresis observed for FK506-induced QT prolongation was successfully analyzed by the present pharmacokinetic/pharmacodynamic model, which may provide a rational basis for developing a clinical dosing regimen to avoid possible QT prolongation induced by FK506.

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Inhibitory effects of the antihistamines epinastine, terfenadine, and ebastine on potassium currents in rat ventricular myocytes

Ohtani H., Hanada E., Hirota M., Sato H., Kotaki H., Sawada Y., Uemura H., Nakaya H., Iga T.

Journal of Pharmacy and Pharmacology (Journal of Pharmacy and Pharmacology) 51 ( 9 ) 1059 - 1063 1999.09

ISSN 00223573

We examined and compared the inhibitory effects of three non-sedating antihistamines, terfenadine, ebastine, and epinastine, on delayed rectifier potassium current (I(K)) and transient outward potassium current (I(to)) of rat isolated ventricular myocytes, using a patch clamp technique. Terfenadine, ebastine and epinastine were found to inhibit I(K) with IC50 values of 5.96, 15.3 and 145 μM, respectively. I(to) was suppressed by epinastine with an IC50 value of 69.5 μM. The order of arrhythmogenicity, assessed by the inhibition of I(K), was ranked as terfenadine > ebastine > epinastine, consistent with that of the potencies of each drug for QT prolongation reported in rats.

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Sustained QT prolongation induced by tacrolimus in guinea pigs

Minematsu T., Ohtani H., Sato H., Iga T.

Life Sciences (Life Sciences) 65 ( 14 ) PL197 - PL202 1999.08

ISSN 00243205

Recently, clinical cases have been reported of QT prolongation and torsades de pointes associated with the use of tacrolimus (FK506). We examined the relationship between QTc prolongation and the pharmacokinetics of FK506 in guinea pigs in order to evaluate the arrhythmogenicity of FK506 in comparison with quinidine (QND). FK506 (0.1 or 0.01 mg/hr/kg) or QND (30 mg/hr/kg) was intravenously infused to guinea pigs and time profiles of drug concentration in blood and QTc interval were examined during and after infusion. Both FK506 and QND evoked a significant QTc prolongation, and the dose-response relationship showed an anti-clockwise hysteresis, FK506-induced QTc prolongation persisted throughout the duration of the experiment despite a decline in the plasma FK506 concentration, whilst QND-induced QTc prolongation disappeared as plasma concentrations decreased. FK506 induced a sustained QTc prolongation in guinea pigs at drug concentrations in blood that correspond to its therapeutic range in human, suggesting that it might be of clinical significance to monitor the electrocardiogram, especially when patients have congenital or acquired QT-prolonging risk factors.

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Pharmacokinetic - pharmacodynamic analysis of the arrhythmogenic potency of a novel antiallergic agent, ebastine, in rats

Ohtani H., Sato H., Iga T., Kotaki H., Sawada Y.

Biopharmaceutics and Drug Disposition (Biopharmaceutics and Drug Disposition) 20 ( 2 ) 101 - 106 1999.02

ISSN 01422782

Ebastine (EBS), a novel nonsedative antiallergic agent, is similar to terfenadine in its chemical structure. However, clinical arrhythmogenicity of EBS remains controversial. In this study, we evaluated the possible arrhythmogenic potency of EBS as assessed by QT prolongation from a pharmacokinetic-pharmacodynamic viewpoint in comparison with that of terfenadine. EBS was intravenously infused into anesthetized rats at a rate of 3.0 or 10 mg/kg/h for 60 min, and electrocardiographic effects were continuously monitored from lead II. The plasma concentrations of EBS and its major metabolite, carebastine, were also measured under the same conditions. When intravenously administered, EBS exhibited QT prolongation in an infusion rate-dependent manner, with a lag time. Pharmacokinetic-pharmacodynamic analysis of EBS based on the effect-compartment model revealed values of EC50, E(max) and EC10 (ms) (where 10 ms of QT prolongation was evoked) of 0.73 μg/ml, 12.5 ms and 2.90 μg/mL, respectively. The EC(10 ms) value of EBS was five times higher than that of terfenadine reported previously In conclusion, EBS was suggested to be less arrhythmogenic than terfenadine.

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Pharmacodynamic analysis of the electrocardiographic interaction between disopyramide and erythromycin in rats

Hanada E., Ohtani H., Kotaki H., Sawada Y., Sato H., Iga T.

Journal of Pharmaceutical Sciences (Journal of Pharmaceutical Sciences) 88 ( 2 ) 234 - 240 1999.02

ISSN 00223549

Disopyramide (DP) is known to induce QT prolongation and Torsades de Pointes (TdP) when administered concomitantly with erythromycin (EM). To define and evaluate quantitatively the arrhythmogenic risk of the concomitant administration of DP and EM, we investigated the influence of EM on the pharmacokinetics and pharmacodynamics of DP in rats. The time profiles of change in QT interval and plasma concentration of each drug were evaluated during and after constant intravenous infusion of DP (6.0 or 15.0 mg/kg/h), EM (4.0 or 8.0 mg/kg/h), and coadministration of DP and EM (DP 6.0 mg/kg/h plus EM 4.0 mg/kg/h). Each agent induced QT prolongation at plasma concentrations within the therapeutic range in humans. DP-induced QT prolongation was proportional to its plasma concentration. In the case of EM, the E(max) model with an 'effect compartment' could explain the relationship between plasma EM concentrations and changes in QT interval. Although coadministration of EM with DP gave enhanced QT prolongation compared to dosing with DP alone, EM did not affect the pharmacokinetics of DP. In conclusion, it was shown that a pharmacodynamic interaction contributes to the electrocardiographic adverse reaction (i.e., QT prolongation)induced by coadministration of DP and EM in rats.

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Effects of hypokalaemia on arrhythmogenic risk of quinidine in rats

Hirota M., Ohtani H., Hanada E., Kotaki H., Sawada Y., Iga T.

Life Sciences (Life Sciences) 62 ( 24 ) 2159 - 2169 1998.05

ISSN 00243205

Plasma potassium concentration plays an important role in the induction of arrhythmia and is closely related to the arrhythmogenicity of various drugs. We quantitatively analyzed the influence of plasma potassium concentration on QT intervals before drug administration and on drug-induced QT prolongation, to estimate the risk of drug-induced arrhythmia under hypokalaemic conditions. The hypokalaemic models were produced by intraperitoneal administration of furosemide and hydrochlorothiazide in male Sprague-Dawley rats. The relationship between the changes in QT intervals and time profiles of plasma quinidine (QND) concentration were analyzed during constant intravenous infusion of QND (10 or 30 mg/kg/h) and post infusion in normal and hypokalaemic rats. The plasma QND concentration reached the therapeutic range (3-7 μg/ml) at the high infusion rate (30 mg/kg/h). No pharmacokinetic differences between normal and hypokalaemic rats were observed. QND induced QT prolongation in parallel with the plasma concentration without hysteresis. Although the potency of QND for QT prolongation was not affected by hypokalaemia, the QT intervals before drug administration were significantly prolonged in hypokalaemic rats (65.90 ± 1.40 vs 56.60 ± 0.748 msec, mean ± SEM, p < 0.0001). Thus, the prolongation of QT intervals before drug administration may act as a risk factor of arrhythmia under hypokalaemic conditions.

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Determination of erythromycin concentrations in rat plasma and liver by high-performance liquid chromatography with amperometric detection

Hanada E., Ohtani H., Kotaki H., Sawada Y., Iga T.

Journal of Chromatography B: Biomedical Applications (Journal of Chromatography B: Biomedical Applications) 692 ( 2 ) 478 - 482 1997.05

ISSN 15726495

A simple method for the quantitative determination of erythromycin (EM) concentrations in rat plasma and liver by high-performance liquid chromatography with amperometric detection was developed. EM was extracted from 200 μl of plasma or liver homogenate sample under sodium hydroxide alkaline conditions with tert.-butyl methyl ether. Oleandomycin was used as an internal standard. The recovery rate of EM was up to 100%. The detector cell potential for the oxidation of EM was +1100 mV. The calibration curves were linear over the concentration ranges 0.1-20.0 μg/ml for plasma and 0.5-100.0 μg/g for liver. The method was applied to the determination of the plasma and liver concentrations of EM in rats after intravenous administration (50 mg/kg dose). The method presented here has proved to be of great use for the investigation of the pharmacokinetic characteristics of EM in small animals such as rats.

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A comparative pharmacokinetic-pharmacodynamic study of the electrocardiographic effects of epinastine and terfenadine in rats

Ohtani H., Kotaki H., Sawada Y., Iga T.

Journal of Pharmacy and Pharmacology (Journal of Pharmacy and Pharmacology) 49 ( 4 ) 458 - 462 1997.04

ISSN 00223573

The effects of epinastine hydrochloride and terfenadine on electrocardiographic (ECG) parameters in rats were investigated from a pharmacokinetic and pharmacodynamic perspective. Epinastine hydrochloride (1 or 3 mg kg-1 h-1) or terfenadine (5, 10 or 15 mg kg-1 h-1) was intravenously infused into rats anaesthetized with methane and α-chloralose. The changes in the QT interval derived from limb lead II and the chest lead, heart rate and PR interval were analysed. The time-course of the plasma drug-concentration of each drug was also investigated. Terfenadine prolonged the QT interval in an infusion-rate-dependent manner; its EC50 value was 792-1039 ng mL-1. An obvious QT prolongation was, moreover, observed even at a plasma terfenadine concentration of 100-200 ng mL-1, which is clinically quite high, but might be achieved under a definite condition such as a restrained terfenadine metabolism. Terfenadine also induced PR prolongation and bradycardia in an infusion-rate dependent manner. Epinastine slightly increased the heart rate, but did not affect any of the other ECG parameters even at a plasma concentration of 400 ng mL-1, which is more than 10 times the maximum concentration attained after an ordinary dosage regimen in man. We conclude that epinastine might have an advantage over terfenadine in avoiding adverse electrocardiographic reactions.

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Pharmacokinetic-pharmacodynamic analysis of the electrocardiographic effects of terfenadine and quinidine in rats

Ohtani H., Hanada E., Yamamoto K., Sawada Y., Iga T.

Biological and Pharmaceutical Bulletin (Biological and Pharmaceutical Bulletin) 19 ( 9 ) 1189 - 1196 1996.09

ISSN 09186158

In establishing a method of electrocardiographic (ECG) measurement for investigating drug-induced ECG changes, we examined the ECG effects and pharmacokinetics of terfenadine (TFN) and quinidine (QND) in rats. The time profiles of the plasma concentration and ECG parameters, such as the QT interval determined from limb lead II (QT-II) and the precordial chest lead (QT-V), heart rate and PR interval, were examined during constant intravenous infusion of TFN (5 or 15 mg/kg/h) or QND sulfate dihydrate (10 or 30 mg/kg/h). Both agents provided significant and concentration-dependent QT prolongation. The plasma concentrations (C10), where 10 ms of QT prolongation was observed, were 1.03 μM for TFN and 5.12 μM for QND, respectively. The calculated plasma unbound concentration of C10 (C(10·f)) was 10.3 nM for TFN and 3.82 μM for QND, which coincides with previously reported in vitro values of IC50 for potassium channels. The drug-induced QT prolongation was quantitatively reproduced in rats within the clinical concentration range. The usefulness of our methodology for the evaluation of arrhythmogenic hazards of the drugs was also demonstrated.

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Toxicodynamic analysis of cardiac effects induced by four cholinesterase inhibitors in rats

Yamamoto K., Shimizu M., Ohtani H., Hayashi M., Sawada Y., Iga T.

Journal of Pharmacy and Pharmacology (Journal of Pharmacy and Pharmacology) 48 ( 9 ) 935 - 939 1996.09

ISSN 00223573

The cardiac effect of edrophonium (2-20 μmol kg-1), pyridostigmine (0.5-5 μmol kg-1), neostigmine (0.05-0.5 μmol kg-1) and ambenonium (0.02-0.3 μmol kg-1) was investigated after intravenous administration to rats. For pyridostigmine and neostigmine, the heart rate decreased in a dose-dependent manner, and then gradually recovered to the basal level at about 10 min. Rapid decrease of heart rate was observed after edrophonium and ambenonium administration, and rapid recovery to the basal level within 1 min. For ambenonium, a dose-dependent tachycardiac response was observed. The time-course of heart rate change was analysed by the effect-compartment model. Significant correlation was observed between bradycardiac EC50 values obtained by effect-compartment model analysis and inhibitory constant (K(i)) to acetylcholinesterase in-vitro, suggesting that the bradycardiac response was induced by inhibition of this enzyme and following elevation of acetylcholine concentration in the synaptic cleft. On the other hand, the tachycardiac EC50 values of edrophonium and ambenonium based on the effect-compartment model analysis were similar to dissociation constants (K(d)) of these drugs to muscarinic receptors in-vitro, suggesting that the tachycardiac activity of these drugs may be associated with antagonistic activity to postsynaptic muscarinic receptors. We conclude that, clinically, edrophonium and ambenonium are safer drugs than pyridostigmine and neostigmine, at least as regards muscarinic side-effects, including bradycardia.

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Quantitative determination of epinastine in plasma by high-performance liquid chromatography

Ohtani H., Kotaki H., Sawada Y., Iga T.

Journal of Chromatography B: Biomedical Applications (Journal of Chromatography B: Biomedical Applications) 683 ( 2 ) 281 - 284 1996.08

ISSN 15726495

A high-performance liquid chromatographic (HPLC) method for the quantitative determination of epinastine, a non-sedating histamine H1 receptor antagonist, in rat plasma, was developed. A 100-μl volume of plasma sample was spiked with a solution of internal standard (diphenidol) and extracted with dichloromethane under alkaline conditions. The extract was applied onto the HPLC system and detected by ultraviolet absorption at a wavelength of 220 nm. The linearity of the calibration curve was preserved over the concentration range of 20-1000 ng/ml. Both intra-assay variation and relative error were less than 5% for the plasma sample containing 50 ng/ml or 1000 ng/ml of epinastine hydrochloride. The analytical method presented here should be useful for the investigation of the pharmacokinetic properties of epinastine, which is of clinical significance.

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Lack of potentiation with felbinac patch on the convulsive toxicity of enoxacin in rats

Ohtani H., Noma S., Kawakami J., Sawada Y., Iga T.

Biological and Pharmaceutical Bulletin (Biological and Pharmaceutical Bulletin) 19 ( 7 ) 995 - 997 1996.07

ISSN 09186158

We investigated the possible potentiation of the convulsive toxicity of enoxacin (ENX) by the concomitant topical application of a felbinac (FLB) patch in rats. A felbinac patch (Seltouch®; 0.5%, 3 cm x 4 cm) was attached on the back of rats where their hair has been removed. ENX was infused from the left jugular vein at 8 h after the application of FLB patch under an unanesthetized and unstrained condition. Blood, CSF and brain samples were collected at the occurrence of convulsion, and ENX concentrations of each part were determined. As a result, no significant potentiation by FLB patch was found in the onset time of convulsion or in the ENX concentration of each part. Moreover, based on the assumption that there are no inter-species differences in ENX concentration in the brain at the occurrence of a convulsion (C(br)), the predicted plasma ENX concentration required to elicit convulsions in humans, which was estimated from the C(br) and K(p) value of ENX in the brain of rats, was 20 times higher than the therapeutic plasma level.

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Antibronchospasmic, tachycardiac, and hypokalaemic effects of L‐isoproterenol in guinea‐pigs

Ohtani H., Yamamoto K., Sawada Y., Iga T.

Biopharmaceutics & Drug Disposition (Biopharmaceutics & Drug Disposition) 16 ( 9 ) 745 - 753 1995.12

ISSN 01422782

The relationship between antibronchospasmic, tachycardiac, or hypokalaemic effects and plasma concentration of L‐isoproterenol (ISP) hydrochloride was investigated in guinea‐pigs in vivo. ISP was infused at the rate of 10, 30, 50, 100, and 300 ng kg−1 min−1. The antibronchospasmic effect was expressed as the attenuation of methacholine‐induced bronchospasm. The EC50 values of ISP for antibronchospasmic and tachycardiac effects were 5.12 nM and 3.95 nM, respectively. Although they were comparable to the values reported in vitro (7.23–0.358 nM, 1.77 nM), the concentration response relationship of ISP for antibronchospasmic effect was quite steep with a slope factor of more than six. Moreover, a decrease in plasma potassium level was not clearly detected. The experimental procedure in our present study was useful for evaluating antibronchospasmic and tachycardiac effects of beta‐agonists. Copyright © 1995 John Wiley & Sons, Ltd.

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Prediction of the therapeutic dose for β-stimulants based on preclinical data: Application of oral dosage forms and aerosols to asthmatic patients

Ito K., Yajima N., Ohtani H., Yamada Y., Nakamura K., Sawada Y., Iga T.

Journal of Pharmacokinetics and Biopharmaceutics (Journal of Pharmacokinetics and Biopharmaceutics) 21 ( 2 ) 133 - 144 1993.04

ISSN 0090466X

The therapeutic doses of β-stimulants in the treatment of bronchial asthma show wide variation among the drugs. In the present study, we tried to construct a system for prediction of the optimum clinical dose of β-stimulants as oral dosage forms and aerosols using the data from preclinical pharmacological studies and pharmacokinetic data in humans. Values of EC50 (drug concentration that gives the half-maximum bronchodilator effect) in the in vitro studies based on isolated trachea of guinea pigs were collected from the literature. The ratios of the EC50 value of each drug to that of isoproterenol were used as the indicator of in vitro pharmacological activity. There were significant correlations between the EC50 ratios and the oral dose or the maximum plasma concentration after single oral administration, but the correlation coefficients were relatively small (r<.9). On the other hand, a linear log-log relationship was observed between the EC50 ratio and the maximum plasma unbound concentration (Cumax) (slope=0.907, r=.955, p<0.001). In the case of aerosols, a good correlation was observed between the EC50 ratio and the dose (slope=0.770, r=.900, p<0.01). The predicted concentration of β-stimulants in the lung after aerosol administration tended to be higher than the Cumax after oral administration, suggesting the contribution of nonspecific binding in the lung tissue. These findings indicate the possibility of predicting the appropriate dose of β-stimulants based on the preclinical pharmacological data and the pharmacokinetic data in humans. © 1993 Plenum Publishing Corporation.

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Information system for therapeutic drug monitoring - Information system in Pharmacy Department

Orii T., Yamamoto K., Sawada Y., Iga T., Ohtani H., Kohda Y.

Japan Journal of Medical Informatics (Japan Journal of Medical Informatics) 12 ( 1 ) 17 - 27 1992.12

ISSN 02898055

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