COMPARISON OF KETOCONAZOLE AND FLUCONAZOLE AS CYTOCHROME-P450 INHIBITORS - USE OF STEADY-STATE INFUSION APPROACH TO ACHIEVE PLASMA CONCENTRATION-RESPONSE RELATIONSHIPS

The ability of two azole antifungal agents, ketoconazole and fluconazo le, to inhibit hepatic cytochrome P450 activity in vivo in the rat has been determined, To make a valid comparison, differences in pharmacok inetic properties between the azoles were accounted for by using an in fusion approach to maintain steady-state plasma concentrations over a range of 1-48 mg/liter. Both compounds showed a maximum inhibitory eff ect, assessed by a reduction in antipyrine clearance, of similar to 75 %. The relationship between steady-state plasma concentration and the degree of inhibition of antipyrine clearance was nonlinear for both az oles. However, the inhibitory effect resulted at lower concentrations for ketoconazole than for fluconazole. Analysis of these data provided K-i values of 3 and 10 mu M, for ketoconazole and fluconazole, respec tively, based on plasma concentration of azole. This difference in act ivity is 2 orders of magnitude greater when K-i values are expressed i n terms of unbound concentration in the blood, which may be more repre sentative of hepatic tissue concentrations. K-i values based on unboun d drug concentration are 0.07 and 8.7 mu M for ketoconazole and flucon azole, respectively, These data confirm the conclusions based on in vi tro findings that ketoconazole is a more inhibitory of mammalian cytoc hrome P450 isoenzymes than fluconazole.