Influence of intravenous methylprednisolone pulse treatment on the disposition of ciclosporin and hepatic CYP3A activity in rats.

We examined the effects of high-dose methylprednisolone (MP) on the disposition of ciclosporin (CsA) and hepatic microsomal CYP3A activity using rats. Methylprednisolone sodium succinate (MPS), a prodrug of MP, was intravenously administered as repeated doses (66.3 mg kg(-1)) for 3 days or as a single dose. In MP-treated rats, a significant increase was observed in the total body clearance (CL(tot)) and elimination rate constant (Ke) of intravenously administered CsA. The enzyme activities of triazolam hydroxylations and erythromycin N-demethylation in hepatic microsomes were also enhanced by about 50% by MP treatment, suggesting that the alteration in the CsA pharmacokinetics was due to significant induction of the hepatic CYP3A responsible for the metabolic conversion of CsA. In contrast, no significant changes in the values of CL(tot) and Ke were found following a single treatment with MP. On the other hand, MP inhibited the CYP3A-mediated triazolam hydroxylations in a concentration-dependent manner. The difference between the in-vivo and in-vitro inhibitory behaviours of MP was attributed to the rapid elimination of MP after biotransformation from MPS because the plasma MP concentration decreased with a half-life of 15 min immediately after reaching a level close to the inhibition constant for the triazolam 4-hydroxylation reaction (32.4 microM). Although there is a general consideration that MP cannot act as an enzyme inducer at maintenance doses, the present results strongly suggest that high-dose MP is likely to interact pharmacokinetically with CsA by inducing hepatic CYP3A. These results may provide basic explanations for the clinical experience that blood CsA levels are reduced during MP pulse therapy.