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-g lycoprotein by cyclosporine, a known inhibitor of CYP3A, at different dosag e levels and lengths of treatment. Rats were given various doses of cyclosp orine 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 th e controls. At the end of the study, liver microsomes were prepared and hep atic P-glycoprotein levels were quantified by Western blot analysis. Signif icant induction of hepatic P-glycoprotein was found in rats given cyclospor ine. Rats administered 30 mg/Kg/d orally and 15 mg/Kg/d subcutaneously show ed 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 p attern of induction of P-glycoprotein was not, however, dependent on the ro ute of administration. Fourteen days after the discontinuation of cyclospor ine treatment, P-glycoprotein levels returned to near the control values. A s a drug efflux transporter, the induction of P-glycoprotein by cyclosporin e may decrease the hepatic metabolism of P-glycoprotein substrates. Therefo re this induction of hepatic P-glycoprotein and suppression of hepatic CYP3 A may have a coordinate effect on the metabolism of cyclosporine. These dat a may help explain the large variability associated with cyclosporine absor ption, metabolism, and circulating blood levels.