Received for publication October 16, 2007.
Revised February 8, 2008.
Accepted for publication February 12, 2008.

Impact of Basolateral Mrp3 (Abcc3) and Mrp4 (Abcc4) on the Hepatobiliary Disposition of Fexofenadine in Perfused Mouse Livers

Abstract

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 fexofenadine is excreted into bile primarily by Mrp2 in mice. In the present study, the role of Mrp3 and Mrp4 in the hepatobiliary disposition of fexofenadine was examined in knockout mice using in situ liver perfusion. Compared to 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 knock-out mice, fexofenadine biliary excretion was impaired, but perfusate recovery was similar to wild-type mice, and more than 2-fold higher than 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.

Key words: ABC transporters, biliary excretion, drug transport, hepatic elimination, hepatic transport, hepatobiliary disposition, hepatobiliary transport, MRP, transporters