Effects of cyclosporin A and itraconazole on the pharmacokinetics of atorvastatin in rats1

Abstract

To evaluate the effects of cyclosporin A and itraconazole, which were used as inhibitors of P-glycoprotein (P-gp) and/or cytochrome P450 (CYP) 3A4 on the pharmacokinetics of atorvastatin in rats. The pharmacokinetic parameters of atorvastatin were measured after intravenous (2 mg/kg) and intragastric (10 mg/kg) administration of atorvastatin in rats, which were pretreated with cyclosporin A (5, 10, and 20 mg/kg) or itraconazole (5, 10, and 20 mg/kg). Compared with the control rats, cyclosporin A and itraconazole altered the pharmacokinetics of atorvastatin significantly. The AUC0-t values of atorvastatin after intragastric administration, pretreated with cyclosporin A (5-20 mg/kg), increased by 32.3%, 61.8%, and 187.2%, respectively, but the CLbile values decreased (P<0.01, 5-20 mg/kg). With pretreatment of itraconazole (5-20 mg/kg), the AUC(0-t) values of atorvastatin increased by 88.2%, 102%, and 123%, respectively, but the CL(bile) values decreased (P<0.01, 5-20 mg/kg). These data indicated that cyclosporin A could be effective in inhibiting the efflux of atorvastatin, and itraconazole could be effective in inhibiting both the metabolism and biliary excretion of atorvastatin.