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Research ArticleArticle

Organic Anion Transporter 1 Is Inhibited by Multiple Mechanisms and Shows a Transport Mode Independent of Exchange

Adam G. Hotchkiss, Tiandai Gao, Usman Khan, Liam Berrigan, Mansong Li, Leslie Ingraham and Ryan M. Pelis
Drug Metabolism and Disposition December 2015, 43 (12) 1847-1854; DOI: https://doi.org/10.1124/dmd.115.065748
Adam G. Hotchkiss
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada
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Tiandai Gao
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada
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Usman Khan
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada
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Liam Berrigan
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada
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Mansong Li
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada
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Leslie Ingraham
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada
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Ryan M. Pelis
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada
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Abstract

The mechanism by which drugs inhibit organic anion transporter 1 (OAT1) was examined. OAT1 was stably expressed in Chinese hamster ovary (CHO) cells, and para-aminohippurate (PAH) and 6-carboxyfluorescein were the substrates. Most compounds (10 of 14) inhibited competitively, increasing the Michaelis constant (Km) without affecting the maximal transport rate (Jmax). Others were mixed-type (lowering Jmax and increasing Km) or noncompetitive (lowering Jmax only) inhibitors. The interaction of a noncompetitive inhibitor (telmisartan) with OAT1 was examined further. Binding of telmisartan to OAT1 was observed, but translocation was not. Telmisartan did not alter the plasma membrane expression of OAT1, indicating that it lowers Jmax by reducing the turnover number. PAH transport after telmisartan treatment and its washout recovered faster in the presence of 10% fetal bovine serum in the washout buffer, indicating that binding of telmisartan to OAT1 and its inhibitory effect are reversible. Together, these data suggest that telmisartan binds reversibly to a site distinct from substrate and stabilizes the transporter in a conformation unfavorable for translocation. In the absence of an exchangeable extracellular substrate, PAH efflux from CHO-OAT1 cells was relatively rapid. Telmisartan slowed PAH efflux, suggesting that some transporter-mediated efflux occurs independent of exchange. Although drug-drug interaction predictions at OAT1 assume competitive inhibition, these data show that OAT1 can be inhibited by other mechanisms, which could influence the accuracy of drug-drug interaction predictions at the transporter. Telmisartan was useful for examining how a noncompetitive inhibitor can alter OAT1 transport activity and for uncovering a transport mode independent of exchange.

Footnotes

    • Received May 27, 2015.
    • Accepted September 11, 2015.
  • This work was supported by the Nova Scotia Health Research Foundation [grant MED-EST-2013-9003].

  • dx.doi.org/10.1124/dmd.115.065748.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (12)
Drug Metabolism and Disposition
Vol. 43, Issue 12
1 Dec 2015
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Research ArticleArticle

OAT1 Is Inhibited by Multiple Mechanisms

Adam G. Hotchkiss, Tiandai Gao, Usman Khan, Liam Berrigan, Mansong Li, Leslie Ingraham and Ryan M. Pelis
Drug Metabolism and Disposition December 1, 2015, 43 (12) 1847-1854; DOI: https://doi.org/10.1124/dmd.115.065748

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Research ArticleArticle

OAT1 Is Inhibited by Multiple Mechanisms

Adam G. Hotchkiss, Tiandai Gao, Usman Khan, Liam Berrigan, Mansong Li, Leslie Ingraham and Ryan M. Pelis
Drug Metabolism and Disposition December 1, 2015, 43 (12) 1847-1854; DOI: https://doi.org/10.1124/dmd.115.065748
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