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 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.
Footnotes
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This work was supported by the National Institutes of Health (GM41935 to K.L.R.B. and CA73728 to G.D.K.) and by the National Cancer Institute (Core Grant CA06927 to Fox Chase Cancer Center).
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.107.019273.
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ABBREVIATIONS: Oatp, organic anion transporting polypeptide; Mrp/MRP, multidrug resistance-associated protein; Abcc2-/-, Mrp2 gene knockout; Abcc3-/-, Mrp3 gene knockout; Abcc2-/-/Abcc3-/-, Mrp2 and Mrp3 double-knockout; WT, wild-type C57BL/6; Abcc4-/-, Mrp4 gene knockout.
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↵1 Current affiliation: Wyeth, Discovery Pharmacokinetics, Andover, MA.
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↵2 Current affiliation: Eli Lilly and Company, Drug Disposition, Indianapolis, IN.
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↵3 Current affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, IL.
- Received October 15, 2007.
- Accepted February 12, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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