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METABOLISM, TRANSPORT, AND PHARMACOGENOMICS

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

School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina

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.

Address correspondence to: Dr. Kim L. R. Brouwer, University of North Carolina School of Pharmacy, Kerr Hall, CB#7360, Chapel Hill, NC 27599-7360. E-mail: kbrouwer{at}unc.edu