In vivo induction of hepatic p-glycoprotein by cyclosporine in the rat.

The objective of the present study was to investigate the regulation of P-glycoprotein by cyclosporine, a known inhibitor of CYP3A, at different dosage levels and lengths of treatment. Rats were given various doses of cyclosporine through oral administration or subcutaneous injection. Each treatment group was studied for 28 days or 28 days followed by 14 days of olive oil vehicle dosing. In each group, rats administered vehicle alone served as the controls. At the end of the study, liver microsomes were prepared and hepatic P-glycoprotein levels were quantified by Western blot analysis. Significant induction of hepatic P-glycoprotein was found in rats given cyclosporine. Rats administered 30 mg/Kg/d orally and 15 mg/Kg/d subcutaneously showed an increase in hepatic P-glycoprotein by 93% (p = 0.0011) and 136% (p < 0.001), respectively. Low doses of cyclosporine also induced P-glycoprotein but not to a significant extent, indicating a dose-dependent effect. The pattern of induction of P-glycoprotein was not, however, dependent on the route of administration. Fourteen days after the discontinuation of cyclosporine treatment, P-glycoprotein levels returned to near the control values. As a drug efflux transporter, the induction of P-glycoprotein by cyclosporine may decrease the hepatic metabolism of P-glycoprotein substrates. Therefore this induction of hepatic P-glycoprotein and suppression of hepatic CYP3A may have a coordinate effect on the metabolism of cyclosporine. These data may help explain the large variability associated with cyclosporine absorption, metabolism, and circulating blood levels.