Steroid-specific effects of ketoconazole on corticosteroid disposition: Unaltered prednisolone elimination

Ketoconazole inhibits the clearance of methylprednisolone by 60 percent and extends cortisol suppression beyond that produced by methylprednisolone alone. This study examined prednisolone pharmacokinetics and cortisol suppression in four healthy male volunteers following administration of prednisone 20 mg. Studies were performed with an without ketoconazole 200 mg po for six days. Blood samples were obtained serially over 24 hours and serum prednisone, prednisolone, and cortisol concentrations were determined by HPLC. Prednisolone clearance before and after ketoconazole therapy was not significantly different (160 ± 38 vs. 148 ± 23 mL/h/kg). In addition, no significant differences were found in mean residence time (5.03 ± 0.69 vs. 6.18 ± 1.77 h), terminal slope (0.23 ± 0.03 vs. 0.19 ± 0.05 h^-1), or volume of distribution (0.79 ± 0.11 vs. 0.84 ± 0.12 L/kg). The ratio of cortisol area under the concentration versus time curve (AUC) 0-24 hours after prednisone administration to the AUC under baseline conditions was used as a measure of adrenal suppression. This ratio was not significantly different after prednisolone with and without ketoconazole (0.40 ± 0.10 vs. 0.45 ± 0.03). Renal excretion of prednisone and prednisolone was not significantly changed with ketoconazole. Based on this preliminary study, ketoconazole minimally alters prednisolone clearance in contrast to the significant ketoconazole-methylprednisolone interaction previously reported.