Azoles and allylamines: the clinical implications of interaction with cytochrome P-450 enzymes

Abstract

Two antimycotic agents, the azole ketoconazole and the allylamine terbinafine (Lamisil), have been examined for their effects on the metabolism of tolbutamide, ethinyloestradiol and cyclosporin 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 μM (tolbutamide hydroxylase), 1.9 μM (ethinyloestradiol 2–hydroxylase), 2.0 μM (cyclosporine N-demethylase) and 2.1 μM (cyclosporine hydroxylase). At 50 μM terbinafine concentration, inhibition was less than 5% for tolbutamide, approximately 12% for both cyclosporin pathways and 30% for ethinyloestradiol. Terbinafine does not have the same inhibitory potential for cytochrome P-450 isozymes as ketoconazole.