Inhibition of human drug metabolizing cytochrome P450 by buprenorphine.
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: CYPlA1/2-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 6beta-hydroxylation. Buprenorphine strongly inhibited the CYP3A4- and CYP2D6-catalyzed reactions with Ki values of 14.7 microM and 21.4 microM, respectively. The analgesic also weakly inhibited specific reactions catalyzed by CYP1A1/2 (Ki=132 microM), CYP2B6 (Ki=133 microM), CYP2C19 (Ki=146 microM), CYP2C8/9 (IC50>300 microM), and CYP2E1 (IC50>300 microM), 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.
Umehara
Ken
K
Department of Drug Metabolism, Drug Safety Research Center, Tokushima Research Institute, Osaka Pharmaceutical Co, Ltd, Kagasuno, Japan. k_umehara@research.otsuka.co.jp
Shimokawa
Yoshihiko
Y
Miyamoto
Gohachiro
G
D002047:Buprenorphine / Q000494:pharmacology*; D002384:Catalysis; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009292:Narcotic Antagonists / Q000494:pharmacology*; D013379:Substrate Specificity
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D009292:Narcotic Antagonists; D002047:Buprenorphine