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.
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.