CYCLOSPORINE SUPPRESSES RAT HEPATIC CYTOCHROME-P450 IN A TIME-DEPENDENT MANNER

Background. Cyclosporine is a potent immunosuppressant known to select ively suppress specific cytochrome P450 (P450) isoforms following chro nic therapy in the rat. Cyclosporine undergoes significant hepatic met abolism in the rat, primarily due to P450 3A isoforms. Hence, alterati ons in hepatic metabolism of cyclosporine may lead to changes in drug pharmacokinetics or pharmacodynamics. The purpose of this study was to examine the temporal effect of chronic cyclosporine dosing on P450 pr otein expression and metabolic activity in a rat model of chronic cycl osporine nephropathy. Methods. Adult male rats were administered cyclo sporine 15 mg/kg/day or vehicle 1 ml/kg/day by subcutaneous injection for up to 28 days. To examine whether or not metabolic activity recove red following drug removal, additional rats were administered cyclospo rine for 28 days followed by vehicle for up to an additional 15 days. Hepatic P450 protein expression and microsomal metabolic activity were measured by Western blot analysis and in vitro steroid hydroxylation, respectively. Results. Cyclosporine trough levels progressively incre ased over the 28 days period and were still measurable for up to 15 da ys after discontinuation. Immunoblot analysis indicated that chronic c yclosporine treatment suppressed P450 3A2 expression and in vitro ster oid hydroxylation in a time-dependent manner. Fifteen days following d iscontinuation of cyclosporine dosing, hepatic metabolic activity and microsomal P450 3A2 levels returned to near pre-dosing levels. Conclus ions. We conclude that the time-dependent P450 suppression by cyclospo rine may at least partially explain the variability in cyclosporine ph armacokinetics. These studies support the hypothesis that hepatic isof orms other than P450 3A2 may be responsible for cyclosporine metabolis m during chronic treatment in the rat.