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Research ArticleArticle

Expression of Organic Anion Transporting Polypeptide 1A2 in Red Blood Cells and Its Potential Impact on Antimalarial Therapy

Andrea Hubeny, Markus Keiser, Stefan Oswald, Gabriele Jedlitschky, Heyo K. Kroemer, Werner Siegmund and Markus Grube
Drug Metabolism and Disposition October 2016, 44 (10) 1562-1568; DOI: https://doi.org/10.1124/dmd.116.069807
Andrea Hubeny
Department of Pharmacology (A.H., G.J., H.K.K., M.G.) and Department of Clinical Pharmacology (M.K., S.O., W.S.) at the Center of Drug Absorption and Transport (C_DAT), University Medicine, Greifswald, Germany
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Markus Keiser
Department of Pharmacology (A.H., G.J., H.K.K., M.G.) and Department of Clinical Pharmacology (M.K., S.O., W.S.) at the Center of Drug Absorption and Transport (C_DAT), University Medicine, Greifswald, Germany
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Stefan Oswald
Department of Pharmacology (A.H., G.J., H.K.K., M.G.) and Department of Clinical Pharmacology (M.K., S.O., W.S.) at the Center of Drug Absorption and Transport (C_DAT), University Medicine, Greifswald, Germany
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Gabriele Jedlitschky
Department of Pharmacology (A.H., G.J., H.K.K., M.G.) and Department of Clinical Pharmacology (M.K., S.O., W.S.) at the Center of Drug Absorption and Transport (C_DAT), University Medicine, Greifswald, Germany
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Heyo K. Kroemer
Department of Pharmacology (A.H., G.J., H.K.K., M.G.) and Department of Clinical Pharmacology (M.K., S.O., W.S.) at the Center of Drug Absorption and Transport (C_DAT), University Medicine, Greifswald, Germany
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Werner Siegmund
Department of Pharmacology (A.H., G.J., H.K.K., M.G.) and Department of Clinical Pharmacology (M.K., S.O., W.S.) at the Center of Drug Absorption and Transport (C_DAT), University Medicine, Greifswald, Germany
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Markus Grube
Department of Pharmacology (A.H., G.J., H.K.K., M.G.) and Department of Clinical Pharmacology (M.K., S.O., W.S.) at the Center of Drug Absorption and Transport (C_DAT), University Medicine, Greifswald, Germany
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Abstract

Important antimalarial drugs, including quinolines, act against blood schizonts by interfering with hemoglobin metabolism. To reach their site of action, these compounds have to cross the plasma membrane of red blood cells (RBCs). Organic cation transporters (OCTs) and organic anion transporting polypeptides (OATPs) are important uptake transporters and interesting candidates for local drug transport. We therefore studied their interaction with antimalarial compounds (quinine, chloroquine, mefloquine, pyrimethamine, artemisinin, and artesunate) and characterized the expression of OATP1A2 and OATP2B1 in RBCs. Competition assays using transporter-overexpressing Madin-Darby canine kidney (MDCKII) cells and the model substrate estrone-3-sulfate identified quinine and chloroquine as potent inhibitors of OATP1A2 function (IC50 quinine: 0.7 ± 1.2 µM; chloroquine: 1.0 ± 1.5 µM), but no or only moderate effects were observed for OATP2B1. Subsequently, quinine was identified as a substrate of OATP1A2 (Km 23.4 µM). The OATP1A2-mediated uptake was sensitive to the OATP1A2-specific inhibitor naringin. Both OATPs were expressed in human RBCs, and ex vivo transport studies demonstrated naringin-sensitive accumulation of quinine in these cells (60 pmol versus 38 pmol/5 × 105 RBCs). Additional transport studies using OCT1–3 and organic cation transporter novel type 1 (OCTN1) indicated only significant quinine uptake by OCT1, which was not detected in RBCs. In conclusion, our data demonstrate expression of OATP2B1 and OATP1A2 in RBCs as well as OATP1A2-mediated uptake of quinine. Therefore, modulation of OATP1A2 function may affect quinine uptake into erythrocytes.

Footnotes

    • Received February 2, 2016.
    • Accepted August 4, 2016.
  • ↵1 Current affiliation: University Medicine Göttingen, Göttingen, Germany.

  • This work was supported by the German Federal Ministry for Education and Research [grant 03IPT612X].

  • dx.doi.org/10.1124/dmd.116.069807.

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

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (10)
Drug Metabolism and Disposition
Vol. 44, Issue 10
1 Oct 2016
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Research ArticleArticle

OATP1A2 and Antimalarial Compounds

Andrea Hubeny, Markus Keiser, Stefan Oswald, Gabriele Jedlitschky, Heyo K. Kroemer, Werner Siegmund and Markus Grube
Drug Metabolism and Disposition October 1, 2016, 44 (10) 1562-1568; DOI: https://doi.org/10.1124/dmd.116.069807

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Research ArticleArticle

OATP1A2 and Antimalarial Compounds

Andrea Hubeny, Markus Keiser, Stefan Oswald, Gabriele Jedlitschky, Heyo K. Kroemer, Werner Siegmund and Markus Grube
Drug Metabolism and Disposition October 1, 2016, 44 (10) 1562-1568; DOI: https://doi.org/10.1124/dmd.116.069807
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