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Research ArticleMetabolism, Transport, and Pharmacogenomics

Substrate-Dependent Ligand Inhibition of the Human Organic Cation Transporter OCT2

Mathew Belzer, Mark Morales, Bhumasamudram Jagadish, Eugene A. Mash and Stephen H. Wright
Journal of Pharmacology and Experimental Therapeutics August 2013, 346 (2) 300-310; DOI: https://doi.org/10.1124/jpet.113.203257
Mathew Belzer
Departments of Physiology (M.B., M.M., S.H.W.) and Chemistry (B.J., E.A.M.), University of Arizona, Tucson, Arizona
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Mark Morales
Departments of Physiology (M.B., M.M., S.H.W.) and Chemistry (B.J., E.A.M.), University of Arizona, Tucson, Arizona
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Bhumasamudram Jagadish
Departments of Physiology (M.B., M.M., S.H.W.) and Chemistry (B.J., E.A.M.), University of Arizona, Tucson, Arizona
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Eugene A. Mash
Departments of Physiology (M.B., M.M., S.H.W.) and Chemistry (B.J., E.A.M.), University of Arizona, Tucson, Arizona
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Stephen H. Wright
Departments of Physiology (M.B., M.M., S.H.W.) and Chemistry (B.J., E.A.M.), University of Arizona, Tucson, Arizona
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Abstract

Organic cation transporter 2 (OCT2) mediates the initial step in renal secretion of organic cations: uptake from the blood, across the basolateral membrane, and into the renal proximal tubule cells. Because of its potential as a target for unwanted drug-drug interactions (DDIs), considerable attention has been directed toward understanding the basis of OCT2 selectivity. These studies typically assess selectivity based on ligand inhibition profiles for OCT2-mediated transport of a probe substrate. However, little attention has been given to the potential influence of the substrate on the profile of ligand inhibition. Here we compared the IC50 values obtained for a set of structurally distinct inhibitors against OCT2-mediated transport of three structurally distinct substrates: 1-methyl-4-phenylpyridinium (MPP); metformin; and a novel fluorescent substrate, N,N,N-trimethyl-2-[methyl(7-nitrobenzo[c][l,2,5]oxadiazol-4-yl)amino]ethanaminium iodide (NBD-MTMA). The median IC50 value for inhibition of MPP transport was 9-fold higher than that for inhibition of metformin transport. Similarly, the median IC50 value for inhibition of MPP transport was 5-fold higher than that for NBD-MTMA transport. However, this was not a systematic difference in inhibitory efficacy; the ratio of IC50 values, MPP versus NBD-MTMA, ranged from 88-fold (ipratropium) to 0.3-fold (metformin). These data show that 1) the choice of OCT2 substrate significantly influences both quantitative and qualitative inhibitory interactions with cationic drugs; and 2) ligand interactions with OCT2 are not restricted to competition for a common ligand binding site, consistent with a binding surface characterized by multiple, possibly overlapping interaction sites. Development of predictive models of DDIs with OCT2 must take into account the substrate dependence of ligand interaction with this protein.

Footnotes

    • Received January 14, 2013.
    • Accepted May 23, 2013.
  • This work was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant 5R01DK58251]; the National Institutes of Health National Institute of Environmental Health Sciences [Grant 5P30E006694]; the National Institutes of Health National Cancer Institute [Grant 5P30CA23074]; and the National Institutes of Health National Heart, Lung, and Blood Institute [Grant 5T32HL07249].

  • dx.doi.org/10.1124.jpet.113.203257.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 346 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 346, Issue 2
1 Aug 2013
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Research ArticleMetabolism, Transport, and Pharmacogenomics

Substrate-Dependent Ligand Inhibition of OCT2

Mathew Belzer, Mark Morales, Bhumasamudram Jagadish, Eugene A. Mash and Stephen H. Wright
Journal of Pharmacology and Experimental Therapeutics August 1, 2013, 346 (2) 300-310; DOI: https://doi.org/10.1124/jpet.113.203257

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Research ArticleMetabolism, Transport, and Pharmacogenomics

Substrate-Dependent Ligand Inhibition of OCT2

Mathew Belzer, Mark Morales, Bhumasamudram Jagadish, Eugene A. Mash and Stephen H. Wright
Journal of Pharmacology and Experimental Therapeutics August 1, 2013, 346 (2) 300-310; DOI: https://doi.org/10.1124/jpet.113.203257
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