METABOLISM OF TERFENADINE ASSOCIATED WITH CYP3A(4) ACTIVITY IN HUMAN HEPATIC MICROSOMES

Terfenadine (Seldane) undergoes extensive metabolism to form azacyclon ol and terfenadine alcohol. Terfenadine alcohol is subsequently metabo lized to azacyclonol and terfenadine acid. Although testosterone 6 bet a-hydroxylation [CYP3A(4)] has been shown to be the principal enzyme i nvolved in the first step in terfenadine's biotransformation (formatio n of azacyclonol and terfenadine alcohol), the enzymes catalyzing the subsequent metabolic steps in the conversion of terfenadine alcohol to azacyclonol and terfenadine acid have not been identified. The purpos e of these studies was to determine the role of cytochrome P450 isofor ms in the biotransformation of terfenadine and terfenadine alcohol. To this end, both terfenadine and its alcohol were incubated with 10 ind ividual human liver microsomal samples that have been characterized fo r major isozyme activities. The metabolites and parent drugs were quan tified by HPLC. The formation of azacyclonol and terfenadine alcohol f rom terfenadine is confirmed-to be catalyzed predominantly by CYP3A(4) isozyme, and the ratio of the rate of terfenadine alcohol formation t o that of azacyclonol is 3:1. Involvement of the CYP3A(4) in terfenadi ne metabolism was further confirmed by the following studies: a) inhib ition of terfenadine alcohol formation by ketoconazole and troleandomy cin, two specific inhibitors of CYP3A(4), and b) time course of terfen adine alcohol formation by cloned human CYP3A(4). When terfenadine alc ohol was used as substrate, both the terfenadine acid and azacyclonol formation were also catalyzed by CYP3A(4) isozyme. However, the rate o f formation of the terfenadine acid metabolite is almost 9 times faste r than that of azacyclonol. The net ratio of terfenadine acid to azacy clonol is 2:1.