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Research ArticleArticle

Complex Pharmacokinetic Behavior of Ezetimibe Depends on Abcc2, Abcc3, and Abcg2

Dirk R. de Waart, Maria L. H. Vlaming, Cindy Kunne, Alfred H. Schinkel and Ronald P. J. Oude Elferink
Drug Metabolism and Disposition August 2009, 37 (8) 1698-1702; DOI: https://doi.org/10.1124/dmd.108.026146
Dirk R. de Waart
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Maria L. H. Vlaming
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Cindy Kunne
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Alfred H. Schinkel
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Ronald P. J. Oude Elferink
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Abstract

Ezetimibe lowers plasma cholesterol levels by inhibiting the uptake of cholesterol in the intestine. Because of the extensive enterohepatic circulation of ezetimibe, relatively low doses are required to be effective. In blood and bile the majority of ezetimibe is present as a glucuronide conjugate, which is formed in the enterocyte. Presently, it is not clear which mechanisms are responsible for this efficient enterohepatic circulation. Abcc2, Abcc3, and Abcg2 are ATP-binding cassette (ABC) transporters that are expressed in both liver and intestine and are capable of transporting glucuronidated compounds. The aim of this study was to investigate the contribution of these transporters in the enterohepatic cycling of ezetimibe glucuronide (Ez-gluc). Transport studies were performed in plasma membrane vesicles from ABCC2-, ABCC3-, and ABCG2-expressing Sf21 insect cells. Furthermore, intestinal explants from wild-type and Abcc3(–/–) mice were used to study vectorial transport in a Ussing chamber setup. Finally, biliary excretion of Ez-gluc was measured in vivo after duodenal delivery of ezetimibe in wild-type, Abcc3(–/–), Abcc2(–/–), Abcg2(–/–), and Abcg2(–/–)/Abcc2(–/–) mice. ABCC3-, ABCC2-, and ABCG2-mediated transport was dose dependently inhibited by Ez-gluc. In the Ussing chamber Ez-gluc recovered from the basolateral side was significantly reduced in duodenal (2.2%), in jejunal (23%), and in ileal (23%) tissue of Abcc3(–/–) mice compared with that in tissues of wild-type mice. Biliary excretion of Ez-gluc was significantly reduced in Abcc3(–/–) (34%), Abcc2(–/–) (56%), and Abcg2(–/–)/Abcc2(–/–) (2.5%) compared with that in wild-type mice. These data demonstrate that the enterohepatic circulation of Ez-gluc strongly depends on the joint function of Abcc3, Abcc2, and Abcg2.

Footnotes

  • This work was supported in part by the Dutch Cancer Society [Grant NKI 2003-2940].

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.108.026146.

  • ABBREVIATIONS: Ez-gluc, ezetimibe glucuronide; ABC, ATP-binding cassette; AUC, area under the curve; HPLC, high-performance liquid chromatography; E217βG, estradiol-17β-glucuronide; MTX, methotrexate.

    • Accepted May 14, 2009.
    • Received December 11, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 37 (8)
Drug Metabolism and Disposition
Vol. 37, Issue 8
1 Aug 2009
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Research ArticleArticle

Complex Pharmacokinetic Behavior of Ezetimibe Depends on Abcc2, Abcc3, and Abcg2

Dirk R. de Waart, Maria L. H. Vlaming, Cindy Kunne, Alfred H. Schinkel and Ronald P. J. Oude Elferink
Drug Metabolism and Disposition August 1, 2009, 37 (8) 1698-1702; DOI: https://doi.org/10.1124/dmd.108.026146

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Research ArticleArticle

Complex Pharmacokinetic Behavior of Ezetimibe Depends on Abcc2, Abcc3, and Abcg2

Dirk R. de Waart, Maria L. H. Vlaming, Cindy Kunne, Alfred H. Schinkel and Ronald P. J. Oude Elferink
Drug Metabolism and Disposition August 1, 2009, 37 (8) 1698-1702; DOI: https://doi.org/10.1124/dmd.108.026146
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