OATP and MRP2-mediated hepatic uptake and biliary excretion of eprosartan in rat and human.

BACKGROUND Eprosartan is an angiotensin II receptor antagonist, used in the treatment of hypertension and heart failure in clinical patients. The objective of this study was to clarify the mechanism underlying hepatic uptake and biliary excretion of eprosartan in rats and humans. METHODS Perfused rat liver in situ, rat liver slices, isolated rat hepatocytes and human organic anion-transporting polypeptide (OATP)-transfected cells in vitro were used in this study. RESULTS Extraction ratio of eprosartan was decreased by rifampicin in perfused rat livers. Uptake of eprosartan in rat liver slices and isolated rat hepatocytes was significantly inhibited by Oatp modulators such as ibuprofen, digoxin, rifampicin and cyclosporine A, but not by tetraethyl ammonium or p-aminohippurate. Uptake of eprosartan in rat hepatocytes indicated a saturable process. Although uptake of eprosartan in OATP1B3-human embryonic kidney cells (HEK) 293 cells was not observed, significant differences in cellular accumulations of eprosartan between vector- and OATP1B1-Madin-Darby canine kidney strain (MDCK) II cells were found in transcellular transport study. Moreover, cumulative biliary excretion rate of eprosartan in the presence of probenecid (Multidrug resistance-associated protein 2 (Mrp2) inhibitor) was significantly decreased in perfused rat livers. Vectorial basal-to-apical transport of eprosartan was also observed in OATP1B1/MRP2 double transfectants. CONCLUSIONS Eprosartan was transported by multiple Oatps (at least Oatp1a1 and Oatp1a4)/Mrp2 in rat and OATP1B1/MRP2, at least, in human.