Comparative effects of two antimycotic agents, ketoconazole and terbinafine on the metabolism of tolbutamide, ethinyloestradiol, cyclosporin and ethoxycoumarin by human liver microsomes in vitro

Abstract

Two antimycotic agents, the azole ketoconazole and the allylamine terbinafine, have been examined for their effects on the metabolism of tolbutamide, ethinyloestradiol, cyclosporin and ethoxycoumarin by human liver microsomes (n = 4) in vitro. Ketoconazole caused marked inhibition of all enzyme activities with mean IC50 values (concentration producing 50% inhibition) of 17.9 microM (tolbutamide hydroxylase), 1.9 microM (ethinyloestradiol 2-hydroxylase), 2.0 microM (cyclosporin N-demethylase), 2.1 microM (cyclosporin hydroxylase) and 25 microM (ethoxycoumarin O-deethylase). At 50 microM terbinafine concentration, inhibition was less than 5% for tolbutamide and ethoxycoumarin, approximately 12% for both cyclosporin pathways and 35% for ethinyloestradiol. Terbinafine does not have the same inhibitory potential for cytochrome P-450 isozymes as ketoconazole.