Cancer chemotherapy and pharmacology · 2015
Effects of cyclosporine A on the hepatobiliary disposition and hepatic uptake of etoposide in an isolated perfused rat liver model.
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Khezrian Mina, Sheikholeslami Behjat, Dadashzadeh Simin, Lavasani Hoda, Rouini Mohammadreza
Аннотация
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 (E h), hepatic clearance (CL h), and half-life (T 1/2) 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 (CL b) 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.
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 (E h), hepatic clearance (CL h), and half-life (T 1/2) 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 (CL b) 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.