Oxidation of Histamine H1 Antagonist Mequitazine is Catalyzed by Cytochrome P450 2D6 in Human Liver Microsomes

• Published in: The Journal of pharmacology and experimental therapeutics 1998-02, Vol.284 (2), p.437-442
• Main Authors: Nakamura, K, Yokoi, T, Kodama, T, Inoue, K, Nagashima, K, Shimada, N, Shimizu, T, Kamataki, T
• Format: Article
• Language: English
• Subjects: 1-Propanol - pharmacology; Caffeine - pharmacology; Chlorzoxazone - pharmacology; Coumarins - pharmacology; Cyclosporine - pharmacology; Cytochrome P-450 CYP2D6 - metabolism; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System - metabolism; Enzyme Inhibitors - pharmacology; Histamine H1 Antagonists - metabolism; Humans; Microsomes, Liver - metabolism; Mixed Function Oxygenases - metabolism; Phenacetin - pharmacology; Phenothiazines - metabolism; Precipitin Tests; Sulfaphenazole - pharmacology; Tolbutamide - pharmacology
• ISSN: 0022-3565; 1521-0103

Mequitazine [10-(3-quinuclidinylmethyl) phenothiazine] is a long-acting and selective histamine H1-receptor antagonist that is mainly biotransformed by human liver microsomes to yield hydroxylated and S-oxidized metabolites. Mequitazine hydroxylase was inhibited by propranolol and quinidine. Lineweaver-Burk plots for the hydroxylation and the S-oxidation indicated that the hydroxylation occurred with a low K m (0.72 ± .26 μM) in human liver microsomes. Microsomes from genetically engineered human B-lymphoblastoid cells expressing cytochrome P450 2D6 (CYP2D6) efficiently metabolized mequitazine to the hydroxylated and S-oxidized metabolites. The results indicate that CYP2D6 isozyme is a major form of CYP responsible for the metabolism of mequitazine in human liver microsomes. Inhibition of CYP3A-catalyzed midazolam 1′-hydroxylase by various histamine H1 antagonists, including mequitazine, suggested that mequitazine and some other histamine H1 antagonists could also be inhibitors of CYP3A in human liver microsomes.