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标题：Inhibition of Human Drug Metabolizing Cytochrome P450 by Buprenorphine
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作者：Ken Umehara ; Yoshihiko Shimokawa ; Gohachiro Miyamoto 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：2002
卷号：25
期号：5
页码：682-685
DOI：10.1248/bpb.25.682
出版社：The Pharmaceutical Society of Japan
摘要：The effects of buprenorphine, a powerful mixed agonist/antagonist analgesic, on several cytochrome P450 (CYP) isoform specific reactions in human liver microsomes were investigated to predict drug interaction of buprenorphine in vivo from in vitro data. The following eight CYP-catalytic reactions were used in this study: CYP1A1/2-mediated 7-ethoxyresorufin O -deethylation, CYP2A6-mediated coumarin 7-hydroxylation, CYP2B6-mediated 7-benzyloxyresorufin O -debenzylation, CYP2C8/9-mediated tolbutamide methylhydroxylation, CYP2C19-mediated S -mephenytoin 4-hydroxylation, CYP2D6-mediated bufuralol 1′-hydroxylation, CYP2E1-mediated chlorzoxazone 6-hydroxylation, and CYP3A4-mediated testosterone 6β-hydroxylation. Buprenorphine strongly inhibited the CYP3A4- and CYP2D6-catalyzed reactions with Ki values of 14.7 μ M and 21.4 μ M , respectively. The analgesic also weakly inhibited specific reactions catalyzed by CYP1A1/2 ( Ki =132 μ M ), CYP2B6 ( Ki =133 μ M ), CYP2C19 ( Ki =146 μ M ), CYP2C8/9 (IC₅₀>300 μ M ), and CYP2E1 (IC₅₀>300 μ M ), but not CYP2A6 mediated pathway. In consideration of the Ki values obtained in this study and the therapeutic concentration of buprenorphine in human plasma, buprenorphine would not be predicted to cause clinically significant interactions with other CYP-metabolized drugs.
关键词：buprenorphine;cytochrome P450 inhibition;in vitro drug–drug interaction;human liver microsome