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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Nucleoside Phosphonate Interactions with Multiple Organic Anion Transporters in Renal Proximal Tubule

David S. Miller
Journal of Pharmacology and Experimental Therapeutics November 2001, 299 (2) 567-574;
David S. Miller
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Abstract

The interactions of two antiviral, acyclic nucleoside phosphonates, adefovir and cidofovir, with xenobiotic transporters was studied in intact killifish (Fundulus heteroclitus) renal proximal tubules by using fluorescent substrates, confocal microscopy, and quantitative image analysis. Both drugs reduced in a concentration-dependent manner the transport of fluorescein on the classical organic anion system and transport of fluorescein-methotrexate on multidrug resistance-associated protein 2 (Mrp2). Neither drug inhibited transport of a fluorescent cyclosporin A derivative on P-glycoprotein. Inhibition of Mrp2-mediated transport was abolished by 50 μM p-aminohippurate, indicating that adefovir and cidofovir entered the cells at the basolateral membrane on the classical organic anion transport system (OAT1). Comparison of the inhibitory potencies of the nucleoside phosphonates with other substrates and inhibitors showed them to be moderate inhibitors of OAT1- and Mrp2-mediated transport.

Footnotes

  • Abbreviations:
    ABC
    ATP-binding cassette
    Mrp2
    multidrug resistance-associated protein 2
    OAT
    organic anion transporter
    FL-MTX
    fluorescein-methotrexate
    FL
    fluorescein
    NBD-CSA
    [N-ε(4-nitrobenzofurazan-7-yl)-d-Lys8]-cyclosporin A
    PAH
    p-aminohippurate
    CSA
    cyclosporin A
    LTC4
    leukotriene C4
    • Received April 27, 2001.
    • Accepted July 12, 2001.
  • U.S. Government
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Journal of Pharmacology and Experimental Therapeutics: 299 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 299, Issue 2
1 Nov 2001
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Nucleoside Phosphonate Interactions with Multiple Organic Anion Transporters in Renal Proximal Tubule

David S. Miller
Journal of Pharmacology and Experimental Therapeutics November 1, 2001, 299 (2) 567-574;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Nucleoside Phosphonate Interactions with Multiple Organic Anion Transporters in Renal Proximal Tubule

David S. Miller
Journal of Pharmacology and Experimental Therapeutics November 1, 2001, 299 (2) 567-574;
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