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Research ArticleArticle

Potent and Selective Inhibition of Plasma Membrane Monoamine Transporter by HIV Protease Inhibitors

Haichuan Duan, Tao Hu, Robert S. Foti, Yongmei Pan, Peter W. Swaan and Joanne Wang
Drug Metabolism and Disposition November 2015, 43 (11) 1773-1780; DOI: https://doi.org/10.1124/dmd.115.064824
Haichuan Duan
Department of Pharmaceutics, University of Washington, Seattle, Washington (H.D., T.H., J.W.); Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., Seattle, Washington (R.S.F.); and Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland (Y.P., P.W.S.)
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Tao Hu
Department of Pharmaceutics, University of Washington, Seattle, Washington (H.D., T.H., J.W.); Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., Seattle, Washington (R.S.F.); and Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland (Y.P., P.W.S.)
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Robert S. Foti
Department of Pharmaceutics, University of Washington, Seattle, Washington (H.D., T.H., J.W.); Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., Seattle, Washington (R.S.F.); and Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland (Y.P., P.W.S.)
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Yongmei Pan
Department of Pharmaceutics, University of Washington, Seattle, Washington (H.D., T.H., J.W.); Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., Seattle, Washington (R.S.F.); and Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland (Y.P., P.W.S.)
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Peter W. Swaan
Department of Pharmaceutics, University of Washington, Seattle, Washington (H.D., T.H., J.W.); Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., Seattle, Washington (R.S.F.); and Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland (Y.P., P.W.S.)
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Joanne Wang
Department of Pharmaceutics, University of Washington, Seattle, Washington (H.D., T.H., J.W.); Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., Seattle, Washington (R.S.F.); and Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland (Y.P., P.W.S.)
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Abstract

Plasma membrane monoamine transporter (PMAT) is a major uptake-2 monoamine transporter that shares extensive substrate and inhibitor overlap with organic cation transporters 1–3 (OCT1–3). Currently, there are no PMAT-specific inhibitors available that can be used in in vitro and in vivo studies to differentiate between PMAT and OCT activities. In this study, we showed that IDT307 (4-(4-(dimethylamino)phenyl)-1-methylpyridinium iodide), a fluorescent analog of 1-methyl-4-phenylpyridinium (MPP+), is a transportable substrate for PMAT and that IDT307-based fluorescence assay can be used to rapidly identify and characterize PMAT inhibitors. Using the fluorescent substrate-based assays, we analyzed the interactions of eight human immunodeficiency virus (HIV) protease inhibitors (PIs) with human PMAT and OCT1–3 in human embryonic kidney 293 (HEK293) cells stably transfected with individual transporters. Our data revealed that PMAT and OCTs exhibit distinct sensitivity and inhibition patterns toward HIV PIs. PMAT is most sensitive to PI inhibition whereas OCT2 and OCT3 are resistant. OCT1 showed an intermediate sensitivity and a distinct inhibition profile from PMAT. Importantly, lopinavir is a potent PMAT inhibitor and exhibited >120 fold selectivity toward PMAT (IC50 = 1.4 ± 0.2 µM) over OCT1 (IC50 = 174 ± 40 µM). Lopinavir has no inhibitory effect on OCT2 or OCT3 at maximal tested concentrations. Lopinavir also exhibited no or much weaker interactions with uptake-1 monoamine transporters. Together, our results reveal that PMAT and OCTs have distinct specificity exemplified by their differential interaction with HIV PIs. Further, we demonstrate that lopinavir can be used as a selective PMAT inhibitor to differentiate PMAT-mediated monoamine and organic cation transport from those mediated by OCT1–3.

Footnotes

    • Received April 14, 2015.
    • Accepted August 17, 2015.
  • This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant GM066233].

  • dx.doi.org/10.1124/dmd.115.064824.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (11)
Drug Metabolism and Disposition
Vol. 43, Issue 11
1 Nov 2015
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Research ArticleArticle

HIV PI interactions with PMAT and OCT1–3

Haichuan Duan, Tao Hu, Robert S. Foti, Yongmei Pan, Peter W. Swaan and Joanne Wang
Drug Metabolism and Disposition November 1, 2015, 43 (11) 1773-1780; DOI: https://doi.org/10.1124/dmd.115.064824

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Research ArticleArticle

HIV PI interactions with PMAT and OCT1–3

Haichuan Duan, Tao Hu, Robert S. Foti, Yongmei Pan, Peter W. Swaan and Joanne Wang
Drug Metabolism and Disposition November 1, 2015, 43 (11) 1773-1780; DOI: https://doi.org/10.1124/dmd.115.064824
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