Effects of cyclosporine A on the hepatobiliary disposition and hepatic uptake of etoposide in an isolated perfused rat liver model.

Abstract

A recirculating isolated perfused rat liver model was used to investigate the hepatobiliary disposition of etoposide and the effects of cyclosporine A (CyA) on the pattern of drug disposition in the bile and uptake in the liver. The portal vein, bile duct, and superior vena cava were cannulated in four groups of rats. The perfusions were conducted in the control group, which only received 10µg/ml etoposide, and the tested groups which received etoposide and CyA in 0.4, 2, and 10mg/kg doses. Perfusate and bile samples were collected up to 180min. The determination of etoposide in the samples and homogenized liver by the high-performance liquid chromatography method showed that the administration of CyA led to significant changes in the hepatic excretion (E h), hepatic clearance (CL h), and half-life (T 1/2) of etoposide in the CyA 2 and 10mg/kg treatment groups but not in 0.4mg/kg group. The volume of the bile decreased to 64 and 45% and biliary clearance (CL b) of etoposide reduced by 73 and 82% in 0.4 and 2mg/kg CyA group, respectively, when compared with the control group. These results demonstrated the dose-dependant non-specific inhibitory effects of CyA on p-glycoproteins, multidrug resistance protein 2, bile salt export pump, and organic anion-transporting polypeptide, the drug transporters responsible for etoposide hepatobiliary disposition, hepatic uptake, and bile formation in rat.