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 fluconazole, to inhibit hepatic cytochrome P450 activity in vivo in the rat has been determined. To make a valid comparison, differences in pharmacokinetic properties between the azoles were accounted for by using an infusion approach to maintain steady-state plasma concentrations over a range of 1-48 mg/liter. Both compounds showed a maximum inhibitory effect, assessed by a reduction in antipyrine clearance, of approximately 75%. The relationship between steady-state plasma concentration and the degree of inhibition of antipyrine clearance was nonlinear for both azoles. However, the inhibitory effect resulted at lower concentrations for ketoconazole than for fluconazole. Analysis of these data provided Ki values of 3 and 10 microM, for ketoconazole and fluconazole, respectively, based on plasma concentration of azole. This difference in activity is 2 orders of magnitude greater when Ki values are expressed in terms of unbound concentration in the blood, which may be more representative of hepatic tissue concentrations. Ki values based on unbound drug concentration are 0.07 and 8.7 microM for ketoconazole and fluconazole, respectively. These data confirm the conclusions based on in vitro findings that ketoconazole is a more inhibitory of mammalian cytochrome P450 isoenzymes than fluconazole.