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

• Published in: Drug metabolism and disposition Vol. 26; no. 8; pp. 818 - 821
• Main Authors: KOBAYASHI, K, YAMAMOTO, T, CHIBA, K, TANI, M, SHIMADA, N, ISHIZAKI, T, KUROIWA, Y
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.08.1998
• Subjects: Alkylation; Analgesics; Analgesics, Opioid - metabolism; B-Lymphocytes - enzymology; Biological and medical sciences; Buprenorphine - metabolism; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; DNA, Complementary - genetics; DNA, Complementary - metabolism; Humans; Isoenzymes - genetics; Isoenzymes - metabolism; Kinetics; Medical sciences; Mixed Function Oxygenases - genetics; Mixed Function Oxygenases - metabolism; Neuropharmacology; Pharmacology. Drug treatments; Human; Buprenorphine; Digestive system; Isozyme; Cytochrome P450; Liver; Opiates; Narcotic analgesic; Metabolism; In vitro
• ISSN: 0090-9556; 1521-009X

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 6β-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 K M 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 K M values) of human liver microsomes and recombinant CYP3A4 provide the most supportive evidence for BN N -dealkylation being catalyzed by CYP3A4.