The Effect of P-Glycoprotein Inhibition and Activation on the Absorption and Serum Levels of Cyclosporine and Tacrolimus in Rats.

BACKGROUND Permeability glycoprotein (P-glycoprotein or P-gp) plays an important role in the intestinal absorption of the immunosuppressive agents: cyclosporine and tacrolimus. OBJECTIVES The aim of this study was to determine how the intestinal absorption of cyclosporine and tacrolimus is affected when they are used with P-gp activating or inhibiting agents. MATERIAL AND METHODS In in vitro experiments, everted parts of rat small intestines were used to evaluate the effects of verapamil (a P-gp inhibitor) and rifampicin (a P-gp inducer) on the intestinal absorption of cyclosporine and tacrolimus. In in vivo experiments, the effects of verapamil and rifampicin on the plasma concentrations of cyclosporine and tacrolimus were evaluated. RESULTS In in vitro experiments, the absorption of cyclosporine and tacrolimus from the small intestine increased in a time-dependent manner when the drugs were administered with or without verapamil or rifampicin. There was no difference in the absorption of cyclosporine ± verapamil/rifampicin between the jejunum and ileum; however, ileal absorption of tacrolimus + rifampicin was significantly higher than jejunal absorption (p < 0.05). Plasma concentrations of cyclosporine and tacrolimus were significantly increased when they were co-administered with verapamil (p < 0.001) and significantly decreased when co-administered with rifampicin (p < 0.05). CONCLUSIONS P-gp may play an important role in the absorption of immunosupressive drugs, and it may contribute to drug-drug interactions thay may lead to inadequate drug response or toxicity.