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Vol. 26, Issue 8, 818-821, August 1998

SHORT COMMUNICATION
Human Buprenorphine N-Dealkylation Is Catalyzed by Cytochrome P450 3A4

Kaoru Kobayashi, Toshinori Yamamoto, Kan Chiba, Masayoshi Tani, Noriaki Shimada, Takashi Ishizaki, and Yukio Kuroiwa

Department of Clinical Pharmacy,
School of Pharmaceutical Sciences,
Showa University (K.K., T.Y., Y.K.);
Laboratory of Biological Toxicology,
Faculty of Pharmaceutical Sciences,
Chiba University (K.C.);
Division of General Surgery,
Department of Surgery (M.T.),
and Division of Drug Metabolism and
Disposition, Department of Clinical
Pharmacology, Research Institute (T.I.),
International Medical Center of Japan;
and Techno-Research Center,
Daiichi Pure Chemicals Co. Ltd. (N.S.)

Buprenorphine (BN) is a thebaine derivative with analgesic properties. To identify and characterize the cytochrome P450 (CYP) enzyme(s) involved in BN N-dealkylation, in vitro studies using human liver microsomes and recombinant human CYP enzymes were performed. Norbuprenorphine formation from BN was measured by a simple HPLC-UV assay method, without extraction. The BN N-dealkylation activities in 10 human liver microsomal preparations were strongly correlated with microsomal CYP3A-specific metabolic reactions, i.e. triazolam 1'-hydroxylation (r = 0.954), midazolam 1'-hydroxylation (r = 0.928), and testosterone 6beta -hydroxylation (r = 0.897). Among the eight recombinant CYP enzymes studied (CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4), only CYP3A4 could catalyze BN N-dealkylation. The apparent KM value for recombinant CYP3A4 was similar to that for human liver microsomes (23.7 vs. 39.3 ± 9.2 µM). The demonstration of BN N-dealkylation by recombinant CYP3A4 and the agreement in the affinities (apparent KM values) of human liver microsomes and recombinant CYP3A4 provide the most supportive evidence for BN N-dealkylation being catalyzed by CYP3A4.

Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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