In vitro biliary clearance of angiotensin II receptor blockers and 3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors in sandwich-cultured rat hepatocytes: Comparison with in vivo biliary clearance

Previous reports have indicated that in vitro biliary clearance (Cl biliary) determined in sandwich-cultured hepatocytes correlates well with in vivo Cl biliary for limited sets of compounds. This study was designed to estimate the in vitro Cl biliary in sandwich-cultured rat hepatocytes (SCRHs) of angiotensin II receptor blockers and HMG-CoA reductase inhibitors that undergo limited metabolism, to compare the estimated Cl biliary values with published in vivo Cl biliary data in rats, and to characterize the mechanism(s) of basolateral uptake and canalicular excretion of these drugs in rats. The average biliary excretion index (BEI) and in vitro Cl biliary values of olmesartan, valsartan, pravastatin, rosuvastatin, and pitavastatin were 15, 19, 43, 45, and 20%, respectively, and 1.7, 3.2, 4.4, 46.1, and 34.6 ml/min/kg, respectively. Cl biliary predicted from SCRHs, accounting for plasma unbound fraction, correlated with reported in vivo Cl biliary for these drugs. The rank order of Cl biliary values predicted from SCRHs was consistent with in vivo Cl biliary values. Bromosulfophthalein inhibited the uptake of all drugs. BEI and Cl biliary values of olmesartan, valsartan, pravastatin, and rosuvastatin, known multidrug resistance-associated protein (Mrp) 2 substrates, were reduced in SCRHs from Mrp2-deficient (TR-) compared with wild-type (WT) rats. Although Mrp2 plays a minor role in pitavastatin biliary excretion, pitavastatin BEI and Cl biliary were reduced in TR- compared with WT SCRHs; Bcrp expression in SCRHs from TR- rats was decreased. In conclusion, in vitro Cl biliary determined in SCRHs can be used to estimate and compare in vivo Cl biliary of compounds in rats and to characterize transport proteins responsible for their hepatic uptake and excretion.