Effect of dose on cyclosporine-induced suppression of hepatic cytochrome P450 3A2 and 2C11.

Cyclosporine is a potent immunosuppressive drug that undergoes extensive hepatic metabolism catalyzed primarily by the cytochrome P450 (P450) 3A enzyme family. Cyclosporine alters its own metabolism by selective suppression of specific P450 isoforms after chronic therapy in rats. Modulation of hepatic P450 by chronic cyclosporine dosing is associated with increased blood concentrations leading to nephropathy. However, the relationship between cyclosporine dose and hepatic enzyme suppression is not known. The purpose of this study was to examine the effect of escalating doses of cyclosporine on P450 regulation and metabolic activity in the rat. Following 1 week of a low-salt diet, rats were given cyclosporine 5, 15, 30 or 50 mg/kg per day or an equal volume of vehicle for 2 weeks via oral gavage. At the end of the dosing period, livers were removed and hepatic microsomes prepared. Hepatic P450 proteins were measured using Western blot analysis and catalytic activity determined by in vitro testosterone hydroxylation. Cyclosporine dosing suppressed both P450 3A2 and 2C11 protein expression and catalytic activity in a dose-dependent manner. Catalytic activity of two other P450 isoforms, 2A1 and 2B1, were unchanged by cyclosporine administration. Thus, the selective suppression of hepatic microsomal P450 by cyclosporine is not only dependent on the length of therapy, but also the dose administered.