| Impact of basolateral multidrug resistance-associated protein (Mrp) 3 and Mrp4 on the hepatobiliary disposition of fexofenadine in perfused mouse livers. | |
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MedLine Citation:
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PMID: 18276836 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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 approximately 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. |
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Authors:
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Xianbin Tian; Brandon Swift; Maciej J Zamek-Gliszczynski; Martin G Belinsky; Gary D Kruh; Kim L R Brouwer |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2008-02-14 |
Journal Detail:
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Title: Drug metabolism and disposition: the biological fate of chemicals Volume: 36 ISSN: 1521-009X ISO Abbreviation: Drug Metab. Dispos. Publication Date: 2008 May |
Date Detail:
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Created Date: 2008-04-21 Completed Date: 2008-08-18 Revised Date: 2011-05-05 |
Medline Journal Info:
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Nlm Unique ID: 9421550 Medline TA: Drug Metab Dispos Country: United States |
Other Details:
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Languages: eng Pagination: 911-5 Citation Subset: IM |
Affiliation:
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School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Bile / metabolism Histamine H1 Antagonists, Non-Sedating / metabolism* Liver / metabolism* Male Mice Mice, Inbred C57BL Mice, Knockout Multidrug Resistance-Associated Proteins / genetics, metabolism* Terfenadine / analogs & derivatives*, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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CA06927/CA/NCI NIH HHS; CA73728/CA/NCI NIH HHS; GM41935/GM/NIGMS NIH HHS; P30 CA006927-46/CA/NCI NIH HHS; R01 GM041935-17/GM/NIGMS NIH HHS; U01 CA073728-08/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Abcc4 protein, mouse; 0/Histamine H1 Antagonists, Non-Sedating; 0/Multidrug Resistance-Associated Proteins; 0/multidrug resistance-associated protein 2; 0/multidrug resistance-associated protein 3; 138452-21-8/fexofenadine; 50679-08-8/Terfenadine |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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