Atorvastatin enhanced the bioavailability of irinotecan by inhibition of permeability-glycoprotein in rats with colon cancer: In vivo and in vitro studies

Abstract

Background: Satins' combination with anticancer drugs is a potential combination in treating cancer, which also inhibits the permeability glycoprotein (P-gp) to reduce the development of drug resistance by altering the absorption kinetics. The objective of the present investigation was to study the effect of atorvastatin (ATS) and verapamil (VER) on the pharmacokinetics of irinotecan (IRT) by N-methyl N-nitroso-urea-induced cancer in rat colon and small intestine. Materials and Methods: An in vitro study using noneverted sac model was conducted to determine the effect of ATS on the functional status of intestinal P-gp in colon cancer-induced rats. IRT (75 μg/ml) with and without VER (200 μM) and ATR (30 μg/ml) were filled into the excised colon tissue. In in vivo study, VER (25 mg/kg, p.o.) and ATS (20 mg/kg, p.o.) were administered separately 2 h before IRT (80 mg/kg, p.o.) dosing in male Wistar rats. Serum samples were collected at 0.5, 1, 2, 4, 6, 8, 10, and 12 h time points from control and treated animals to determine IRT concentration. Results: An in vitro noneverted sac study indicated IRT to be a P-gp substrate, and the function of intestinal P-gp was significantly inhibited in the presence of VER and ATS. After oral TRT dosing, the mean area under the plasma concentration-time curve was found to be 1.406 ± 0.15, which was increased significantly, i.e., 2.376 ± 0.19 (P < 0.001) and 1.856 ± 0.07 (P < 0.01), when VER and ATS, respectively, were co-administered with IRT. Similarly, the mean maximum plasma concentration of IRT increased from 0.247 ± 0.02 μg/ml (IRT alone) to 0.390 ± 0.03 (P < 0.001) (with VER) to 0.321 ± 0.02 (P < 0.01) (with ATS). Conclusion: These results indicate the improved bioavailability of IRT by the P-gp inhibitory effect of ATS, and further investigation is needed to develop IRT oral formulation in combination with suitable P-gp inhibitors for the treatment of colon cancer.