著者

丹羽 俊朗 本田 真司 白川 清治 今村 靖 大崎 定行 高木 明

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学雑誌 (ISSN:00155691)

巻号頁・発行日

vol.128, no.2, pp.93-103, 2006 (Released:2006-08-31)

参考文献数

144

被引用文献数

2 2

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選択的セロトニン再取り込み阻害薬フルボキサミンの薬物相互作用に関するin vitro阻害試験および臨床試験の報告を総説としてまとめた.まず,各cytochrome P450(CYP)の代表的な基質であることが知られている薬物に対するin vitro阻害試験および臨床試験結果を整理した.In vitro阻害試験において,フルボキサミンはCYP2A6,CYP2C9,CYP2D6,CYP2E1およびCYP3A4に比べCYP1A2およびCYP2C19を強く阻害し,臨床試験での阻害効果はCYP1A2>CYP2C19>CYP3A4>CYP2C9>CYP2D6(阻害無し)の順である.次に,国内にてフルボキサミンと併用される約80種の薬物(特に血糖降下薬および高血圧治療薬)とフルボキサミンとの薬物相互作用のin vitro阻害試験および臨床試験の報告を調査したが,いずれも一部の薬物で検討されているのみであった.そこで,それぞれの薬物の代謝に関与する薬物代謝酵素および尿中未変化体排泄率を調査したが,主にフルボキサミンにより阻害されるCYP(特にCYP1A2およびCYP2C19)で代謝される薬物ではフルボキサミンとの併用の際には注意を要し,代謝を受けにくく尿中未変化体排泄率が高い薬物ではフルボキサミンによる薬物相互作用を受けにくいことが推察される.したがって,フルボキサミンとの併用治療を行う際には,併用薬の薬物動態を考慮し,CYP阻害による薬物相互作用を起こしにくい併用薬を選択する必要があると考えられる.

著者

丹羽 俊朗 柳井 檀 杉本 静也 雫 真里菜

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学会年会要旨集 第92回日本薬理学会年会 (ISSN:24354953)

巻号頁・発行日

pp.3-P-128, 2019 (Released:2020-03-20)

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[Purpose] CYP2D catalyze dopamine formation from p- and m-tyramine in the brain, and human CYP2D6 is polymorphic Imipramine, a tricyclic antidepressant, and fluvoxamine, an SSRI, are CYP2D6 inhibitors. Dopamine formation from p-tyramine mediated by CYP2D6 variants, CYP2D6.2 and CYP2D6.10 was compared, and the effect of genetic polymorphism on the inhibitory effects of antidepressants was investigated.[Methods] CYP2D6.1, CYP2D6.2, and CYP2D6.10 expressed in recombinant Escherichia coli were used. Dopamine formation from p-tyramine in the presence of antidepressants such as imipramine, desipramine, fluvoxamine, fluoxetine, and paroxetine was determined by HPLC.[Results] CYP2D6.10 had higher Michaelis constants of dopamine formation than CYP2D6.1 and CYP2D6.2. Inhibition constant of imipramine and desipramine against CYP2D6.10 were higher than that against CYP2D6.1. Fluoxetine and paroxetine inhibited CYP2D6.1-mediated dopamine formation. The maximal velocity for all CYP2D6 variants gradually increased with increasing fluvoxamine concentrations. [Conclusions] CYP2D6 polymorphism might affect the inhibitory effect of antidepressants on dopamine formation in the brain.

著者

丹羽 俊朗 白神 歳文 高木 明

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.125, no.10, pp.795-805, 2005-10-01 (Released:2005-10-01)

参考文献数

81

被引用文献数

22 25

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This article reviews the in vitro metabolic and the in vivo pharmacokinetic drug-drug interactions with antifungal drugs, including fluconazole, itraconazole, micafungin, miconazole, and voriconazole. In the in vitro interaction studies, the effects of antifungal drugs on specific activities of cytochrome P450s (CYPs), including CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4, in human liver microsomes are compared to predict the possibility of drug interactions in vivo. Fluconazole, micafungin, and voriconazole have lower inhibitory effects on CYP3A4 activities than itraconazole and miconazole, and IC50 and/or Ki values against CYP2C9 and CYP2C19 activities are the lowest for miconazole, followed by voriconazole and fluconazole. In in vivo pharmacokinetic studies, it is well known that itraconazole is a potent clinically important inhibitor of the clearance of CYP3A4 substrates, and fluconazole and voriconazole are reported to increase the blood or plasma concentrations of not only midazolam and cyclosporine (CYP3A4 substrates) but also of phenytoin (CYP2C9 substrate) and/or omeprazole (CYP2C19/CYP3A4 substrate). On the other hand, no inhibition of CYP activities except for CYP3A4 activity by micafungin is observed in vitro, and the blood concentrations of cyclosporine and tacrolimus are not affected by coadministration of micafungin in vivo, suggesting that micafungin would not cause clinically significant interactions with drugs that are metabolized by CYPs via the inhibition of metabolism. Miconazole is a potent inhibitor of all CYPs investigated in vitro, although there are few detailed studies on the clinical significance of this except for CYP2C9. Therefore the differential effects of these antifungal drugs on CYP activities must be considered in the choice of antifungal drugs in patients receiving other drugs.