Effect of itraconazole on the pharmacokinetics of prednisolone and methylprednisolone and cortisol secretion in healthy subjects

Aims Itraconazole is a potent inhibitor of CYP3A4 activity and is often use d in combination with corticosteroids. Since the latter are partly metaboli zed by CYP3A4, we studied the interaction between itraconazole, prednisone and methylprednisolone in healthy male subjects. Methods The effects of 4 days administration of oral itraconazole (400 mg o n the first day then 200 mg day(-1) for 3 days) on the pharmacokinetics of prednisolone after a single oral dose of prednisone (60 mg) and the pharmac okinetics of methylprednisolone after single oral dose of methylprednisolon e (48 mg) were studied in II healthy male subjects in a two-period cross-ov er trial. Plasma cortisol concentrations were determined as a pharmacodynam ic index. Results Itraconazole increased the mean area under the methylprednisolone c oncentration-time curve from 2773 ng ml(-1) h to 7011 ng ml(-1) h (P<0.001) and the elimination half-life from 3.2 h to 5.5 h (P<0.001). The pharmacok inetics of prednisolone were unchanged. Cortisol concentrations at 24 h wer e lower after administration of methylprednisolone with itraconazole than a fter methylprednisolone alone (24 ng ml(-1) vs 109 ng ml(-1), P<0.001). Conclusions Itraconazole increased methylprednisolone concentrations marked ly with enhanced suppression of endogenous cortisol secretion, but had no e ffect on prednisolone pharmacokinetics. The pharmacokinetic interaction bet ween methylprednisolone and itraconazole is probably related to inhibition of hepatic CYP3A4 activity by itraconazole.