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Research ArticleArticle

Interaction of Macrolide Antibiotics with Intestinally Expressed Human and Rat Organic Anion-Transporting Polypeptides

Tian Lan, Anuradha Rao, Jamie Haywood, Charles B. Davis, Chao Han, Eric Garver and Paul A. Dawson
Drug Metabolism and Disposition December 2009, 37 (12) 2375-2382; DOI: https://doi.org/10.1124/dmd.109.028522
Tian Lan
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Anuradha Rao
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Jamie Haywood
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Charles B. Davis
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Chao Han
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Eric Garver
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Paul A. Dawson
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Abstract

The macrolide antibiotics azithromycin and clarithromycin are large molecular weight compounds that exhibit moderate to excellent oral bioavailability in preclinical species and humans. Previous concomitant dosing studies in rats using rifamycin SV, a general organic anion-transporting polypeptide (OATP) inhibitor, suggested that the high oral absorption of azithromycin and clarithromycin may be caused by facilitative uptake by intestinal Oatps. In this study, we used OATP/Oatp-expressing cells to investigate the interaction of macrolides with rat Oatp1a5, human OATP1A2, and human/rat OATP2B1/Oatp2b1. These experiments showed that azithromycin and clarithromycin were potent inhibitors of rat Oatp1a5-mediated taurocholate uptake with apparent inhibitor constant (Ki) values of 3.3 and 2.4 μM, respectively. The macrolides functioned as noncompetitive inhibitors but were not transport substrates for rat Oatp1a5, as assessed by direct uptake measurements of radiolabeled azithromycin and clarithromycin. cis-Inhibition and direct uptake studies further showed that azithromycin and clarithromycin were only very weak inhibitors and not substrates for human OATP1A2 and human/rat OATP2B1/Oatp2b1. In summary, these results indicate that the macrolides azithromycin and clarithromycin potently inhibit rat Oatp1a5 but do not significantly interact with OATP1A2 and OATP2B1/Oatp2b1. These intestinally expressed OATP/Oatp(s) are not responsible for the postulated facilitative uptake of azithromycin and clarithromycin, and alternative facilitative pathways must exist for their intestinal absorption.

Footnotes

  • This work was supported in part by National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant F32-DK079576]; and GlaxoSmithKline.

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

    doi:10.1124/dmd.109.028522

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

  • OATP (human) or Oatp (rodent)
    organic anion-transporting polypeptide
    AUC
    area under the blood-concentration time curve
    MDCK
    Madin-Darby canine kidney
    BSP
    bromosulfophthalein
    PBS
    phosphate-buffered saline
    DMEM
    Dulbecco's modified Eagle's medium
    CI
    confidence interval.

    • Received May 19, 2009.
    • Accepted September 3, 2009.
  • Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 37 (12)
Drug Metabolism and Disposition
Vol. 37, Issue 12
1 Dec 2009
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Research ArticleArticle

Interaction of Macrolide Antibiotics with Intestinally Expressed Human and Rat Organic Anion-Transporting Polypeptides

Tian Lan, Anuradha Rao, Jamie Haywood, Charles B. Davis, Chao Han, Eric Garver and Paul A. Dawson
Drug Metabolism and Disposition December 1, 2009, 37 (12) 2375-2382; DOI: https://doi.org/10.1124/dmd.109.028522

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Research ArticleArticle

Interaction of Macrolide Antibiotics with Intestinally Expressed Human and Rat Organic Anion-Transporting Polypeptides

Tian Lan, Anuradha Rao, Jamie Haywood, Charles B. Davis, Chao Han, Eric Garver and Paul A. Dawson
Drug Metabolism and Disposition December 1, 2009, 37 (12) 2375-2382; DOI: https://doi.org/10.1124/dmd.109.028522
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