Abstract
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 Km (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.
Footnotes
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Send reprint requests to: Dr. Tetsuya Kamataki, Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Hokkaido University, N12W6, Sapporo 060 Japan.
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1 This work was supported in part by a Grant-in-Aid from the Ministry of Education, Science, Sports and Culture of Japan.
- Abbreviations:
- CYP
- cytochrome P450
- FMO
- flavin-containing monooxygenase
- HPLC
- high-performance liquid chromatography
- PM
- poor metabolizer
- EM
- extensive metabolizer
- Received June 13, 1997.
- Accepted October 6, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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