Effects of Cyclosporine a on the Hepatobiliary Disposition and Hepatic Uptake of Etoposide in an Isolated Perfused Rat Liver Model Publisher Pubmed



Khezrian M¹ ; Sheikholeslami B² ; Dadashzadeh S³ ; Lavasani H¹ ; Rouini M¹ Show Affiliations
Source: Cancer Chemotherapy and Pharmacology Published:2015

Abstract

Purpose: 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. Methods: 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 10 μg/ml etoposide, and the tested groups which received etoposide and CyA in 0.4, 2, and 10 mg/kg doses. Perfusate and bile samples were collected up to 180 min. Results: 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 (Eh), hepatic clearance (CLh), and half-life (T1/2) of etoposide in the CyA 2 and 10 mg/kg treatment groups but not in 0.4 mg/kg group. The volume of the bile decreased to 64 and 45 % and biliary clearance (CLb) of etoposide reduced by 73 and 82 % in 0.4 and 2 mg/kg CyA group, respectively, when compared with the control group. Conclusions: 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. © 2015 Springer-Verlag Berlin Heidelberg.