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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

The Impact of Plasma Protein Binding on the Renal Transport of Organic Anions

Daniel A. J. Bow, Jennifer L. Perry, John D. Simon and John B. Pritchard
Journal of Pharmacology and Experimental Therapeutics January 2006, 316 (1) 349-355; DOI: https://doi.org/10.1124/jpet.105.093070
Daniel A. J. Bow
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Jennifer L. Perry
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John D. Simon
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John B. Pritchard
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Abstract

Drugs and xenobiotics bind to plasma proteins with varying degrees of affinity, and the amount of binding has a direct effect on free drug concentration and subsequent pharmacokinetics. Multiple active and facilitative transport systems regulate the excretion of anionic compounds from the blood in excretory and barrier tissues. Assumptions are made about in vivo substrate affinity and route of elimination based on data from plasma protein-free in vitro assays, particularly following expression of cloned transporters. Ochratoxin A (OTA), a fungal mycotoxin, is a high-affinity substrate for several renal secretory organic anion transporters (OATs), and literature suggests that this elimination pathway is the route of entry leading to proximal tubule-targeted toxicity. However, OTA is known to bind to several plasma proteins with a high affinity, particularly serum albumin, which may impact elimination. In this study, we have systematically examined the handling of OTA and other organic anions, estrone sulfate (ES) and methotrexate (MTX), by OATs in the presence of serum albumin. Increasing concentrations of albumin markedly reduced uptake of OTA by both Xenopus laevis oocytes expressing OATs 1, 3, and 4 and organic anion-transporting polypeptide 1. For all transporters tested, virtually all mediated OTA uptake was eliminated by an albumin concentration equivalent to 10% of that present in the blood plasma. Thus, OTA uptake is dependent on the free substrate concentration and severely limited by binding to human serum albumin. MTX and ES uptake were likewise dependent on free concentration.

Footnotes

  • This work was supported by the Intramural Research Program of the National Institutes of Health and National Institute of Environmental Health Sciences.

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

  • doi:10.1124/jpet.105.093070.

  • ABBREVIATIONS: PAH, p-aminohippuric acid; GFR, glomerular filtration rate; OTA, ochratoxin A; OAT, organic anion transporter; r, rat; OATP, organic anion-transporting polypeptide; h, human; ES, estrone sulfate; MTX, methotrexate; HSA, human serum albumin.

    • Received July 22, 2005.
    • Accepted September 28, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 316 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 316, Issue 1
1 Jan 2006
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

The Impact of Plasma Protein Binding on the Renal Transport of Organic Anions

Daniel A. J. Bow, Jennifer L. Perry, John D. Simon and John B. Pritchard
Journal of Pharmacology and Experimental Therapeutics January 1, 2006, 316 (1) 349-355; DOI: https://doi.org/10.1124/jpet.105.093070

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

The Impact of Plasma Protein Binding on the Renal Transport of Organic Anions

Daniel A. J. Bow, Jennifer L. Perry, John D. Simon and John B. Pritchard
Journal of Pharmacology and Experimental Therapeutics January 1, 2006, 316 (1) 349-355; DOI: https://doi.org/10.1124/jpet.105.093070
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