PT  - JOURNAL ARTICLE
AU  - Katsunori Nakamura
AU  - Tsuyoshi Yokoi
AU  - Takao Kodama
AU  - Kazuaki Inoue
AU  - Kazuo Nagashima
AU  - Noriaki Shimada
AU  - Toshiaki Shimizu
AU  - Tetsuya Kamataki
TI  - Oxidation of Histamine H1 Antagonist Mequitazine is Catalyzed by Cytochrome P450 2D6 in Human Liver Microsomes
DP  - 1998 Feb 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 437--442
VI  - 284
IP  - 2
4099  - http://jpet.aspetjournals.org/content/284/2/437.short
4100  - http://jpet.aspetjournals.org/content/284/2/437.full
SO  - J Pharmacol Exp Ther1998 Feb 01; 284
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics