Metabolism of terfenadine associated with CYP3A(4) activity in human hepatic microsomes.

Terfenadine (Seldane) undergoes extensive metabolism to form azacyclonol and terfenadine alcohol. Terfenadine alcohol is subsequently metabolized to azacyclonol and terfenadine acid. Although testosterone 6 beta-hydroxylation [CYP3A(4)] has been shown to be the principal enzyme involved in the first step in terfenadine's biotransformation (formation 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 purpose of these studies was to determine the role of cytochrome P450 isoforms in the biotransformation of terfenadine and terfenadine alcohol. To this end, both terfenadine and its alcohol were incubated with 10 individual human liver microsomal samples that have been characterized for major isozyme activities. The metabolites and parent drugs were quantified by HPLC. The formation of azacyclonol and terfenadine alcohol from terfenadine is confirmed to be catalyzed predominantly by CYP3A(4) isozyme, and the ratio of the rate of terfenadine alcohol formation to that of azacyclonol is 3:1. Involvement of the CYP3A(4) in terfenadine metabolism was further confirmed by the following studies: a) inhibition of terfenadine alcohol formation by ketoconazole and troleandomycin, two specific inhibitors of CYP3A(4), and b) time course of terfenadine alcohol formation by cloned human CYP3A(4). When terfenadine alcohol was used as substrate, both the terfenadine acid and azacyclonol formation were also catalyzed by CYP3A(4) isozyme. However, the rate of formation of the terfenadine acid metabolite is almost 9 times faster than that of azacyclonol. The net ratio of terfenadine acid to azacyclonol is 2:1.