Ketoconazole inhibits cyclosporine metabolism in vivo in mice.

Several case reports have suggested that ketoconazole, an antifungal drug, inhibits the metabolism of cyclosporine, an immunosuppressant drug used in patients undergoing organ transplantation. We have used a mouse model to study this possible pharmacokinetic interaction. Eight mice received 95 mg/kg of ketoconazole p.o. for 3 days; eight mice, receiving vehicle only, served as controls. A therapeutic 2.6 mg/kg dose plus a radiolabeled tracer dose of cyclosporine were administered as a bolus i.v. injection. Blood samples were drawn sequentially over 7 hr. Unchanged cyclosporine and metabolites were extracted and concentrated from whole blood with ether. After separation from metabolites using high-performance liquid chromatography, the concentration of unchanged cyclosporine was determined from its radioactivity. A comparison of the pharmacokinetic parameters of unchanged drug between control and treated animals showed that pretreatment with ketoconazole inhibited the metabolism of cyclosporine. In the presence of ketoconazole, cyclosporine clearance decreased from 15.4 to 7.6 ml/hr; terminal half-life increased from 4.1 to 11.2 hr; and steady-state volume of distribution did not change significantly. If a similar phenomenon occurs in humans, these findings could have important clinical implications. Although the therapeutic range for cyclosporine has not been clearly established, cyclosporine toxicity may be related to elevated concentrations. Therefore, patients who receive the combination of cyclosporine and ketoconazole should have blood levels of cyclosporine and signs of toxicity monitored closely.