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Research ArticleArticle

Oral Availability of Cefadroxil Depends on ABCC3 and ABCC4

Dirk R. de Waart, Koen van de Wetering, Cindy Kunne, Suzanne Duijst, Coen C. Paulusma and Ronald P. J. Oude Elferink
Drug Metabolism and Disposition March 2012, 40 (3) 515-521; DOI: https://doi.org/10.1124/dmd.111.041731
Dirk R. de Waart
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Koen van de Wetering
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Cindy Kunne
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Suzanne Duijst
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Coen C. Paulusma
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Ronald P. J. Oude Elferink
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Abstract

Some cephalosporins, such as cefadroxil, are orally available. H+-coupled peptide transporter 1 mediates the transport of cephalosporins across the apical membrane of enterocytes. It is not known which mechanism(s) is responsible for the subsequent transport of cephalosporins across the basolateral membrane toward the circulation. We have tested whether ATP-binding cassette (ABC) transporters ABCC3 and/or ABCC4 are involved in the latter process. Transport experiments with plasma membrane vesicles expressing these transporters were used to determine whether ABCC3 and ABCC4 can transport cephalosporins in vitro. The involvement of Abcc3 and Abcc4 in the transport of cefadroxil from enterocytes was subsequently studied using intestinal explants from wild-type, Abcc3(−/−), Abcc4(−/−), and Abcc3(−/−)/Abcc4(−/−) mice in an Ussing chamber setup. Finally, appearance of cefadroxil in portal blood was investigated in vivo after intrajejunal administration of cefadroxil in wild-type, Abcc3(−/−), Abcc4(−/−), and Abcc3(−/−)/Abcc4(−/−) mice.

ABCC3- and ABCC4-mediated transport of estradiol-17β-glucuronide was dose-dependently inhibited by cephalosporins in vesicular transport experiments. Furthermore, transport of cefadroxil by ABCC3 and ABCC4 was saturable with Km values of 2.5 ± 0.7 and 0.25 ± 0.07 mM, respectively. Transport of cefadroxil from the apical to the basolateral side of jejunal tissue explants was unchanged in Abcc3(−/−) but significantly reduced (approximately 2-fold) in Abcc4(−/−) and Abcc3(−/−)/Abcc4(−/−) when compared with wild-type tissue. Upon instillation of cefadroxil in the jejunum, portal and peripheral blood concentrations were similar in Abcc3(−/−) and Abcc4(−/−) but approximately 2-fold reduced in Abcc3(−/−)/Abcc4(−/−) compared with wild-type mice. Our data demonstrate that intestinal absorption of cefadroxil depends partly on ABCC3 and ABCC4.

Footnotes

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

    http://dx.doi.org/10.1124/dmd.111.041731.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    PepT1
    H+-coupled peptide transporter 1
    E217βG
    estradiol-17β-glucuronide
    HPLC
    high-performance liquid chromatography
    Sf21
    Spodoptera frugiperda 21
    Mrp
    multidrug resistance-associated protein.

  • Received July 11, 2011.
  • Accepted December 13, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (3)
Drug Metabolism and Disposition
Vol. 40, Issue 3
1 Mar 2012
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Research ArticleArticle

TRANSPORT OF CEFADROXILBY ABCC3 AND ABCC4

Dirk R. de Waart, Koen van de Wetering, Cindy Kunne, Suzanne Duijst, Coen C. Paulusma and Ronald P. J. Oude Elferink
Drug Metabolism and Disposition March 1, 2012, 40 (3) 515-521; DOI: https://doi.org/10.1124/dmd.111.041731

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Research ArticleArticle

TRANSPORT OF CEFADROXILBY ABCC3 AND ABCC4

Dirk R. de Waart, Koen van de Wetering, Cindy Kunne, Suzanne Duijst, Coen C. Paulusma and Ronald P. J. Oude Elferink
Drug Metabolism and Disposition March 1, 2012, 40 (3) 515-521; DOI: https://doi.org/10.1124/dmd.111.041731
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