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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Nonsteroidal Anti-Inflammatory Drugs Efficiently Reduce the Transport and Cytotoxicity of Adefovir Mediated by the Human Renal Organic Anion Transporter 1

Andrew S. Mulato, Edmund S. Ho and Tomas Cihlar
Journal of Pharmacology and Experimental Therapeutics October 2000, 295 (1) 10-15;
Andrew S. Mulato
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Edmund S. Ho
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Tomas Cihlar
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Abstract

Adefovir is a nucleotide analog with anti-human immunodeficiency virus (HIV) activity that has been extensively studied in clinical trials. While on prolonged anti-HIV therapy with adefovir, some patients may develop drug-associated nephrotoxicity manifested by changes in laboratory markers of renal tubular functions that are reversible upon drug discontinuation. It has been recently shown that adefovir is efficiently transported by the human renal organic anion transporter 1 (hOAT1), a membrane transport protein localized in the kidney, that presumably mediates the accumulation of adefovir in renal proximal tubules. In an effort to look for novel inhibitors of this transport process, we used a cell line stably expressing hOAT1 to demonstrate that nonsteroidal anti-inflammatory drugs (NSAIDs) efficiently inhibit hOAT1-specific transport of adefovir at clinically relevant concentrations. Diflunisal, ketoprofen, flurbiprofen, indomethacin, naproxen, and ibuprofen were equally or more effective (IC50 = 0.85–8 μM) than probenecid or betamipron, two known potent inhibitors of hOAT1 (IC50 = 8 and 6 μM, respectively) with in vivo nephroprotective effects. Importantly, NSAIDs significantly reduced the shift in adefovir cytotoxicity observed upon hOAT1 expression with ketoprofen and naproxen being 2- to 3-times more effective than probenecid. Transport experiments with [3H]ketoprofen and [3H]ibuprofen revealed that NSAIDs themselves were not efficiently transported by hOAT1. None of the NSAIDs tested showed any interference with the anti-HIV activity of adefovir. In conclusion, these observations suggest that NSAIDs may reduce or delay the emergence of adefovir nephrotoxicity.

Footnotes

  • Send reprint requests to: Tomas Cihlar, Gilead Sciences, 333 Lakeside Dr., Foster City, CA 94404. E-mail:tomas_cihlar{at}gilead.com

  • Abbreviations:
    OAT1
    organic anion transporter 1
    PAH
    p-aminohippuric acid
    hOAT1
    human renal organic anion transporter 1
    NSAIDs
    nonsteroidal anti-inflammatory drugs
    CHO
    Chinese hamster ovary
    CHOhOAT
    CHO cells stably expressing hOAT1
    CHOpIRES
    CHO cells stably transfected with the expression vector pIRES-neo
    • Received March 14, 2000.
    • Accepted May 31, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 295 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 295, Issue 1
1 Oct 2000
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Nonsteroidal Anti-Inflammatory Drugs Efficiently Reduce the Transport and Cytotoxicity of Adefovir Mediated by the Human Renal Organic Anion Transporter 1

Andrew S. Mulato, Edmund S. Ho and Tomas Cihlar
Journal of Pharmacology and Experimental Therapeutics October 1, 2000, 295 (1) 10-15;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Nonsteroidal Anti-Inflammatory Drugs Efficiently Reduce the Transport and Cytotoxicity of Adefovir Mediated by the Human Renal Organic Anion Transporter 1

Andrew S. Mulato, Edmund S. Ho and Tomas Cihlar
Journal of Pharmacology and Experimental Therapeutics October 1, 2000, 295 (1) 10-15;
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