OXIDATION OF HISTAMINE H1 ANTAGONIST MEQUITAZINE IS CATALYZED BY CYTOCHROME-P450 2D6 IN HUMAN LIVER-MICROSOMES

Mequitazine [10-(3-quinuclidinylmethyl) phenothiazine] is a long-actin g and selective histamine H1-receptor antagonist that is mainly biotra nsformed by human liver microsomes to yield hydroxylated and S-oxidize d metabolites. Mequitazine hydroxylase was inhibited by propranolol an d quinidine. Lineweaver-Burk plots for the hydroxylation and the S-oxi dation indicated that the hydroxylation occurred with a low K-m (0.72 +/- .26 mu M) in human liver microsomes. Microsomes from genetically e ngineered 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 m ajor form of CYP responsible for the metabolism of mequitazine in huma n liver microsomes. Inhibition of CYP3A-catalyzed midazolam 1'-hydroxy lase by various histamine H1 antagonists, including mequitazine, sugge sted that mequitazine and some other histamine H1 antagonists could al so be inhibitors of CYP3A in human liver microsomes.