Involvement of multiple human cytochromes P450 in the liver microsomal metabolism of astemizole and a comparison with terfenadine

Aims The aims of the present study were to investigate the metabolism of as temizole in human liver microsomes, to assess possible pharmacokinetic drug -interactions with astemizole and to compare its metabolism with terfenadin e, a typical H-1 receptor antagonist known to be metabolized predominantly by CYP3A4. Methods Astemizole or terfenadine were incubated with human liver microsome s or recombinant cytochromes P450 in the absence or presence of chemical in hibitors and antibodies. Results Troleandomycin, a CYP3A4 inhibitor, markedly reduced the oxidation of terfenadine (26% of controls) in human liver microsomes, but showed only a marginal inhibition on the oxidation of astemizole (81% of controls). Th ree metabolites of astemizole were detected in a liver microsomal system, i .e. desmethylastemizole (DES-AST), 6-hydroxyastemizole (6OH-AST) and norast emizole (NOR-AST) at the ratio of 7.4:2.8:1. Experiments with recombinant P 450s and antibodies indicate a negligible role for CYP3A4 on the main metab olic route of astemizole, i.e. formation of DES-AST, although CYP3A4 may me diate the relatively minor metabolic routes to 6OH-AST and NOR-AST. Recombi nant CYP2D6 catalysed the formation of 6OH-AST and DES-AST. Studies with hu man liver microsomes, however, suggest a major role for a mono P450 in DES- AST formation. Conclusions In contrast to terfenadine, a minor role for CYP3A4 and involve ment of multiple P450 isozymes are suggested in the metabolism of astemizol e. These differences in P450 isozymes involved in the metabolism of astemiz ole and terfenadine may associate with distinct pharmacokinetic influences observed with coadministration of drugs metabolized by CYP3A4.