The disposition of methylprednisolone was examined in six normal subjects after the injection of 20 mg iv methylprednisolone sodium succinate. Disposition studies were performed both without and with ketoconazole, 200 mg/day, for 6 days. Ketoconazole increased the methylprednisolone AUC and mean residence time (by 135% and 66%, respectively) and decreased clearance (60%), the terminal phase slope, and the volume of distribution. These findings are typical of macrolide antibiotic alteration of methylprednisolone disposition and consistent with reports of inhibition of drug metabolism by ketoconazole. Methylprednisolone reduced the 24-hour cortisol AUC by 44%, but morning cortisol concentrations returned to normal. Ketoconazole with methylprednisolone further reduced the 24-hour cortisol AUC and suppressed morning cortisol concentrations. Thus ketoconazole inhibits methylprednisolone disposition and extends the adrenal suppression effects of this corticosteroid.