COMPARATIVE EFFECTS OF THE ANTIMYCOTIC DRUGS KETOCONAZOLE, FLUCONAZOLE, ITRACONAZOLE AND TERBINAFINE ON THE METABOLISM OF CYCLOSPORINE BY HUMAN LIVER-MICROSOMES

Four antimycotic drugs, the azoles ketoconazole, itraconazole and fluconazole, and the allylamine terbinafine have been studied for their effect on the metabolism of cyclosporin by human liver microsomes (n = 3) in vitro. Ketoconazole caused marked inhibition of cyclosporin hydroxylase (to metabolites M17 and M1) with IC50 and K(i) values of 0.24 +/- 0.01 and 0.022 +/- 0.004-mu-M, respectively. Based on IC50 values, itraconazole was ten times less potent (IC50 value of 2.2 +/- 0.2-mu-M) and both fluconazole and terbinafine had values above 100-mu-M. K(i) values for itraconazole and fluconazole were 0.7 +/- 0.2 and 40 +/- 5.6-mu-M, respectively. No kinetic parameters were calculated for terbinafine because of the lack of inhibitory effects. Based on these data, ketoconazole is confirmed as being a potent inhibitor of cyclosporin metabolism and this has clinical relevance. Although inhibition by fluconazole was much less than that by itraconazole at equimolar concentrations, it should be noted that in patients plasma concentrations of fluconazole are much greater than those of itraconazole. Clinical interactions of cyclosporin with both fluconazole and itraconazole have been reported. In contrast to the azoles, terbinafine does not have the same potential for interaction.