Details of a Researcher - Ohtani, Hisakazu

Papers - Ohtani, Hisakazu

Division display 41 - 60 of about 214 ／ All the affair displays >>

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.

Access to Document (DOI)

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.

Access to Document (DOI)

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.

Access to Document (DOI)

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.

Access to Document (DOI)

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.

Access to Document (DOI)

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.

Access to Document (DOI)

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.

Access to Document (DOI)

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.

Access to Document (DOI)

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.

Access to Document (DOI)

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.

Access to Document (DOI)

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.

Access to Document (DOI)

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.

Access to Document (DOI)

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.

Access to Document (DOI)

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).

Access to Document (DOI)

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).

Access to Document (DOI)

　 Previous page - Next page 　