論文 - 大谷　壽一

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.

International Journal of Clinical Pharmacology and Therapeutics （International Journal of Clinical Pharmacology and Therapeutics）  51(5) （ 5 ） 374-382 - 382 2013年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  09461965

　概要を見る

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年09月

研究論文（学術雑誌）, 共著, 査読有り

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.

British Journal of Clinical Pharmacology （British Journal of Clinical Pharmacology）  73(2) （ 2 ） 248-256 - 256 2012年02月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  03065251

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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年12月

ISSN  02694727

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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年10月

ISSN  00316903

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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.

Biopharmaceutics and Drug Disposition （Biopharmaceutics and Drug Disposition）  32(9) （ 9 ） 498-506 - 506 2011年10月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  01422782

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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年10月

研究論文（学術雑誌）, 共著, 査読有り

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年10月

ISSN  0031-6903

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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年09月

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

Akiyoshi T., Saito T., Murase S., Miyazaki M., Murayama N., Yamazaki H., Guengerich F.P., Nakamura K., Yamamoto K., Ohtani H.

Drug Metabolism and Disposition （Drug Metabolism and Disposition）  39(4) （ 4 ） 724-8 - 728 2011年04月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  00909556

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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年03月

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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年07月

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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年07月

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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年07月

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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年06月

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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年06月

研究論文（学術雑誌）, 共著, 査読有り

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年06月

ISSN  09461965

　概要を見る

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年04月

研究論文（学術雑誌）, 共著, 査読有り

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 Metabolism and Pharmacokinetics （Drug Metabolism and Pharmacokinetics）  25(2) （ 2 ） 170-179 - 179 2010年04月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  13474367

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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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大谷壽一.

医薬品情報学 （日本医薬品情報学会）  11(3)   192-195 2010年02月

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