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0090-9556/03/3106-768-772$20.00
DMD 31:768-772, 2003

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INTERACTION OF BUPRENORPHINE AND ITS METABOLITE NORBUPRENORPHINE WITH CYTOCHROMES P450 IN VITRO

Wenjiang Zhang, Yamini Ramamoorthy, Rachel F. Tyndale, and Edward M. Sellers

Departments of Pharmacology (W.Z., Y.R., R.F.T., E.M.S.), Psychiatry (E.M.S.), and Medicine (E.M.S.), University of Toronto, Ontario, Canada; Center for Addiction and Mental Health, Toronto, Ontario, Canada (E.M.S.); and Sunnybrook and Women's Health Science Centre, Toronto, Ontario, Canada (E.M.S.)

Buprenorphine is a thebaine derivative used in the treatment of heroin and other opiate addictions. In this study, the selective probe reactions for each of the major hepatic cytochromes P450 (P450s) were used to evaluate the effect of buprenorphine and its main metabolite norbuprenorphine on the activity of these P450s. The index reactions used were CYP1A2 (phenacetin O-deethylation), CYP2A6 (coumarin 7-hydroxylation), CYP2C9 (diclofenac 4'-hydroxylation), CYP2C19 (omeprazole 5-hydrxoylation), CYP2D6 (dextromethorphan O-demethylation), CYP2B6 (7-ethoxy-4-trifluoromethyl-coumarin 7-deethylation), CYP2E1 (chlorzoxazone 6-hydroxylation), and CYP3A4 (omeprazole sulfoxidation). Buprenorphine exhibited potent, competitive inhibition of CYP2D6 (Ki 10 ± 2 µM and 1.8 ± 0.2 µM) and CYP3A4 (Ki 40 ± 1.6 µM and 19 ± 1.2 µM) in microsomes from human liver and cDNA-expressing lymphoblasts, respectively. Compared with buprenorphine, norbuprenorphine demonstrated a lower inhibitory potency with CYP2D6 (22.4% inhibition at 20 µM norbuprenorphine) and CYP3A4 (13.6% inhibition at 20 µM) in microsomes from human cDNA-expressing lymphoblast cells. Furthermore, buprenorphine was shown to be a substrate of CYP2D6 (Km = 600 µM; Vmax = 0.40 nmol/min/mg protein) and CYP3A4 (Km = 36 µM; Vmax = 0.19 nmol/min/mg protein). The present in vitro study suggests that buprenorphine and its major metabolite norbuprenorphine are inhibitors of CYP2D6 and CYP3A4; however, at therapeutic concentrations they are not predicted to cause potentially clinically important drug interactions with other drugs metabolized by major hepatic P450s.

Address correspondence to: Dr. Edward M. Sellers, 340 College Street Suite 400, Toronto, ON M5T 3A9 Canada. E-mail: e.sellers{at}utoronto.ca




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