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Impact of Basolateral Multidrug Resistance-Associated Protein (Mrp) 3 and Mrp4 on the Hepatobiliary Disposition of Fexofenadine in Perfused Mouse Livers

School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (X.T., B.S., M.J.Z.-G., K.L.R.B.); and Medical Science Division, Fox Chase Cancer Center, Philadelphia, Pennsylvania (M.G.B., G.D.K.)

The disposition of fexofenadine, a commonly used antihistamine drug, is governed primarily by active transport. Biliary excretion of the parent compound is the major route of systemic clearance. Previous studies demonstrated that fexofenadine hepatic uptake is mediated by organic anion transporting polypeptides. Recently, we showed that in mice fexofenadine is excreted into bile primarily by multidrug resistance-associated protein (Mrp) 2 (Abcc2). In the present study, the roles of Mrp3 (Abcc3) and Mrp4 (Abcc4) in the hepatobiliary disposition of fexofenadine were examined in knockout mice using in situ liver perfusion. Compared with that in wild-type mice, basolateral excretion of fexofenadine was impaired, resulting in a 50% decrease in perfusate recovery in Abcc3^-/- mice; in contrast, fexofenadine hepatobiliary disposition was unaltered in Abcc4^-/- mice. As expected, in Abcc2^-/- mice, fexofenadine was redirected from the canalicular to the basolateral membrane for excretion. In Abcc2^-/-/Abcc3^-/- double-knockout mice, fexofenadine biliary excretion was impaired, but perfusate recovery was similar to that in wild-type mice and more than 2-fold higher than that in Abcc3^-/- mice, presumably due to compensatory basolateral transport mechanism(s). These results demonstrate that multiple transport proteins are involved in the hepatobiliary disposition of fexofenadine. In addition to Mrp2 and Mrp3, other transport proteins play an important role in the biliary and hepatic basolateral excretion of this zwitterionic drug.