Plasma concentrations and effects of oral methylprednisolone are considerably increased by itraconazole

Background Methylprednisolone is a widely used glucocorticoid. In this study, a possible interaction of itraconazole, a potent inhibitor of CYP3A4, with orally administered methylprednisolone was examined. Methods In this double‐blind, randomized, 2‐phase crossover study, 10 healthy volunteers received either 200 mg itraconazole or placebo orally once a day for 4 days. On day 4, each subject ingested a dose of 16 mg methylprednisolone. Plasma concentrations of methylprednisolone, cortisol, itraconazole, and hydroxyitraconazole were determined by HPLC up to 24 hours. Results Itraconazole increased the total area under the plasma methylprednisolone concentration‐time curve 3.9‐fold compared with placebo (1968 ± 470 ng · hr/mL versus 520 ± 125 ng · hr/mL [mean ± SD]; P < .001). The peak plasma concentration of methylprednisolone was increased 1.9‐fold (221 ± 49 ng/mL versus 118 ± 25 ng/mL; P < .001), and its elimination half‐life was increased 2.4‐fold (4.4 ± 0.7 hours versus 1.9 ± 0.3 hours; P < .001) by itraconazole. The mean plasma cortisol concentration during the itraconazole phase, measured 24 hours after ingestion of methylprednisolone, was only about 13% of that during the placebo phase (18 ± 23 ng/mL versus 139 ± 60 ng/mL; P < .001). Conclusions Itraconazole considerably increases plasma concentrations and effects of oral methylprednisolone, probably by inhibiting its CYP3A4‐mediated metabolism. Care should be taken if itraconazole or other potent inhibitors of CYP3A4 are used concomitantly with oral methylprednisolone, particularly during long‐term use. Clinical Pharmacology & Therapeutics (1998) 64, 363–368; doi: