Details of a Researcher - Ohtani, Hisakazu

Papers - Ohtani, Hisakazu

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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 2025.12

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

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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Proton Pump Inhibitors Attenuate the Effectiveness of Nivolumab Monotherapy in Patients with Advanced Gastric Cancer: A Retrospective Study.

Yamaguchi M, Kawazoe H, Kasai Y, Hirata K, Ohtani H

Journal of Gastrointestinal Cancer (Springer) 56 ( 1 ) 226 2025.11

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

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Inhibition kinetics of citrus jabara juice and its components on CYP2C9 activity

Koinuma K., Morita T., Uekusa Y., Kikuchi H., Imaoka A., Akiyoshi T., Ohtani H.

Journal of Pharmaceutical Sciences 114 ( 11 ) 103983 2025.11

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

Our previous studies demonstrated that the ethyl acetate extract of the juice of jabara (JEx), a Japanese citrus fruit, inhibited cytochrome P450 (CYP) 3A4 activity in a time-dependent manner, but does not inhibit CYP2C19 activity. Its components, 3,3′,4′,5,6,7,8-heptamethoxyflavone (HpMF) and 3,3′,4′,5,6,7-hexamethoxyflavone (HxMF), have been shown to be responsible for this CYP3A4 inhibition. This study aimed to investigate the nature of CYP2C9 inhibition by JEx, HpMF, and HxMF. The time-dependent inhibition kinetics of JEx against human recombinant CYP2C9 were investigated in vitro using warfarin as a substrate. The time-independent inhibition kinetics of JEx, HpMF, and HxMF against CYP2C9 were also determined. JEx did not cause time-dependent inhibition of CYP2C9, while JEx, HpMF, and HxMF inhibited CYP2C9 activity in a time-independent manner with IC<inf>50</inf> values of 2.65 % equivalent, 16.2 µM, and 57.8 µM, respectively. HpMF and HxMF were considered to be primarily responsible for CYP2C9 inhibition by JEx. The ingestion of 250 mL of jabara juice was estimated to reduce intestinal CYP2C9 activity to 3 % of the control value assuming of dilution with 210 mL of intestinal fluid, suggesting that jabara juice may cause food-drug interactions via intestinal CYP2C9 inhibition.

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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

Last author, Accepted, 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

Research paper (scientific journal), Joint Work, Last author, Corresponding author, 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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Identification of risk factors and development of a predictive model in patients using cefmetazole for international normalized ratio elevation

Namiki T., Yokoyama Y., Kimura M., Fukuda S., Seyama S., Iketani O., Samura M., Ishikawa H., Jibiki A., Kawazoe H., Ohtani H., Hasegawa N., Matsumoto K., Hashi H., Suzuki S., Nakamura T.

Plos One 20 ( 7 July ) e0322909 2025.07

Research paper (scientific journal), Joint Work, Accepted

Patient risk factors related to coagulopathy and bleeding when using cefmetazole (CMZ) have not yet been identified, and no models exist to predict side effects during CMZ treatment. Moreover, reports that examine which patients should be careful when using CMZ to ensure safety are lacking. Our objective was to understand risk factors for elevated international normalized ratio (INR) in patients using CMZ and to develop a predictive model for INR elevation using a risk score to enable safe administration of CMZ. This multicenter, retrospective, and observational study was conducted in Tokyo Bay Urayasu Ichikawa Medical Center and Keio University Hospital using data from patients being treated with CMZ. Patients were classified into INR-elevated or non-INR-elevated groups. Univariate and multivariate analyses were performed to calculate the adjusted odds ratios (aOR) and 95% confidence intervals (CI). The actual probability of an elevated INR and probability of an elevated INR predicted by the regression β coefficients were calculated and classified into four categories according to the risk score. Binomial logistic regression analysis revealed that liver disorder (aOR, 5.65; 95% CI, 1.69–18.91; risk scores, 2), nutritional risk (aOR, 6.32; 95% CI, 3.14–12.74; risk scores, 2), no-diabetes mellitus (aOR, 4.53; 95% CI, 1.34–15.26; risk scores, 2), and warfarin use (aOR, 98.44; 95% CI, 7.05–1375.50; risk scores, 5) were significantly associated with INR elevation. The predicted incidence probabilities of INR elevation were<5% (low risk), 5–<30% (medium risk), 30–<90% (high risk), and ≥ 90% (very high risk). The model validity showed a good fit (AUC, 0.79; 95% CI, 0.73–0.85, P<0.001). We identified risk factors that contribute to INR elevation and constructed a model to predict INR elevation using the risk score. Using this predictive model enables the appropriate use of CMZ in a safe manner.

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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

Joint Work, Accepted, 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.

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

Research paper (scientific journal), Joint Work, Last author, Corresponding author, Accepted, 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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Performance improvement of a natural language processing system to extract information from patients' complaints in pharmacist records -Effects of additional training using community pharmacy data-

Ohno, Y; Kiyomiya, K; Nishiyama, T; Aramaki, E; Ohtani, H

AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY 82 S2452 - S2453 2025.01

Last author, ISSN 1079-2082

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

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

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

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

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

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

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

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