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 (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.
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Acknowledgments
This study was part of a bio-pharmaceutical and pharmacological thesis supported by Tehran University of Medical Sciences.
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The authors declare that they have no conflict of interest.
Ethical approval
All procedures performed in studies involving animals were in accordance with the ethical standards of the Animal Ethic Committee and Institutional Review Board of Pharmaceutical Research Centre of Tehran University of Medical Sciences.
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Khezrian, M., Sheikholeslami, B., Dadashzadeh, S. et al. Effects of cyclosporine A on the hepatobiliary disposition and hepatic uptake of etoposide in an isolated perfused rat liver model. Cancer Chemother Pharmacol 75, 961–968 (2015). https://doi.org/10.1007/s00280-015-2719-6
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DOI: https://doi.org/10.1007/s00280-015-2719-6