Diltiazem and mibefradil increase the plasma concentrations and greatly enhance the adrenal-suppressant effect of oral methylprednisolone

Objective: To examine the possible interaction of the calcium channel blockers diltiazem and mibefradil with orally administered methylprednisolone. Methods: In this randomized, double-blind, placebo-controlled, three-phase crossover study, nine healthy subjects received 60 mg diltiazem three times a day, 50 mg mibefradil once a day, or placebo orally for 3 days. On day 3, each subject received a 16 mg oral dose of methylprednisolone. Plasma concentrations of methylprednisolone and cortisol were determined by HPLC up to 47 hours. Results: Compared with placebo, diltiazem and mibefradil increased the total area under the plasma concentration-time curve of methylprednisolone [AUC(0-infinity)] 2.6-fold (P < .001) and 3.8-fold (P < .001), the peak plasma concentration 1.6-fold (P <.001) and 1.8-fold (P < .001), and the elimination half-life 1.9-fold (P < .001) and 2.7-fold (P < .001), respectively. The nighttime exposure to methylprednisolone [AUC(12-23)] was increased 28.2-fold (P <.01) and 72.1-fold (P < .001) by diltiazem and mibefradil, respectively, and correlated negatively (r = -0.81, P < .001) with the morning plasma cortisol concentration (measured at 8 AM, 23 hours after the administration of methylprednisolone). During the diltiazem phase, the morning plasma cortisol concentration was 12% of that during the placebo phase (P <.001); during the mibefradil phase, the morning plasma cortisol concentration was 2% of that during the placebo phase (P < .001). Conclusions: Coadministration of diltiazem or mibefradil with methylprednisolone resulted in increased plasma concentrations and a greatly enhanced adrenal-suppressant effect of oral methylprednisolone. Care should be taken if methylprednisolone is coadministered with a potent CYP3A4 inhibitor for a long period.