Abstract

To determine whether the clinical adverse interactions of terfenadine with azole antifungals and macrolide antibiotics may be related to inhibition of terfenadine biotransformation, an in vitro system was developed to follow the metabolism of terfenadine by rat liver S9 or human liver microsomes. When test compounds were coincubated with terfenadine, the metabolites formed and unchanged terfenadine was quantitatively analyzed by HPLC. Five metabolites of terfenadine were formed by rat liver S9: predominantly alcohol metabolite (III), with four minor metabolites--azacyclonol (I), acid metabolite (II), an unidentified metabolite (IV), and a new ketone metabolite (V). By human liver microsomes, two major metabolites were formed: azacyclonol (I) and alcohol metabolite (III). Ketoconazole, fluconazole, itraconazole, erythromycin, clarithromycin, and troleandomycin potently inhibited terfenadine metabolism by human liver (IC50 = 4-10 microM), but inhibition by rat liver was weaker (IC50 = 87-218 microM) and 18% maximally for troleandomycin. Other CYP3A substrates (cyclosporin A, naringenin, and midazolam) also demonstrated potent inhibition of terfenadine biotransformation in human liver microsomes (IC50 = 17-24 microM). Substrates of other P450 families [sparteine (CYP2D6), caffeine (CYP1A), and diclofenac (CYP2C)] only very weakly inhibited terfenadine metabolism. Dixon plot analyses for human liver revealed competitive/reversible inhibition by the azole antifungals and macrolide antibiotics of azacyclonol and alcohol metabolite formations.(ABSTRACT TRUNCATED AT 250 WORDS)