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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Comparison of “Type I” and “Type II” Organic Cation Transport by Organic Cation Transporters and Organic Anion-Transporting Polypeptides

Jessica E. van Montfoort, Michael Müller, Geny M. M. Groothuis, Dirk K. F. Meijer, Hermann Koepsell and Peter J. Meier
Journal of Pharmacology and Experimental Therapeutics July 2001, 298 (1) 110-115;
Jessica E. van Montfoort
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Michael Müller
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Geny M. M. Groothuis
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Dirk K. F. Meijer
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Hermann Koepsell
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Peter J. Meier
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Abstract

Previous inhibition studies with taurocholate and cardiac glycosides suggested the presence of separate uptake systems for small “type I” (system1) and for bulky “type II” (system2) organic cations in rat hepatocytes. To identify the transport systems involved in type I and type II organic cation uptake, we compared the organic cation transport properties of the rat and human organic cation transporter 1 (rOCT1; hOCT1) and of the organic anion-transporting polypeptides 2 and A (rat Oatp2; human OATP-A) in cRNA-injectedXenopus laevis oocytes. Based on characteristiccis-inhibition patterns of rOCT1-mediated tributylmethylammonium and Oatp2-mediated rocuronium uptake, rOCT1 and Oatp2 could be identified as the organic cation uptake systems1 and 2, respectively, in rat liver. While hOCT1 exhibited similar transport properties as rOCT1, OATP-A- but not Oatp2-mediated rocuronium uptake was inhibited by the OATP-A substrateN-methyl-quinidine. The latter substrate was also transported by rOCT1 and hOCT1, demonstrating distinct organic cation transport activities for rOCT1 and Oatp2 and overlapping organic cation transport activities for hOCT1 and OATP-A. Finally, the data demonstrate that unmethylated quinidine is transported by rOCT1, hOCT1, and OATP-A at pH 6.0, but not at pH 7.5, indicating that quinidine requires a positive charge for carrier-mediated uptake into hepatocytes. In conclusion, the studies demonstrate that in rat liver the suggested organic cation uptake systems1 and 2 correspond to rOCT1 and Oatp2, respectively. However, the rat-based type I and II organic cation transporter classification cannot be extended without modification from rat to human.

Footnotes

  • This work was supported by the Swiss National Science Foundation (Grant 3100-045536.95 to P.J.M.). J.E.v.M. was supported by an Ubbo Emmius scholarship of the University of Groningen. A preliminary report of this study was presented at the 35th Annual Meeting of the European Association for the Study of the Liver (EASL) in Rotterdam, April 29–May 3, 2000, and published in abstract form [JHepatol32 (Suppl 2):118].

  • Abbreviations:
    TEA
    tetraethylammonium
    TBuMA
    tributylmethylammonium
    PAEB
    procainamide ethobromide
    APM
    azidoprocainamide methoiodide
    rOCT1
    rat organic cation transporter 1
    Oatp2
    rat organic anion-transporting polypeptide 2
    APDA
    N-(4,4-azo-n-pentyl)-21-deoxyajmalinium
    hOCT1
    human organic cation transporter 1
    OATP-A
    human organic anion-transporting polypeptide A
    QD
    quinidine
    APQ
    N-(4,4-azo-n-pentyl)-quinuclidine
    NMQ
    N-methyl-quinine
    NMQD
    N-methyl-quinidine
    • Received January 16, 2001.
    • Accepted March 16, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 298 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 298, Issue 1
1 Jul 2001
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Comparison of “Type I” and “Type II” Organic Cation Transport by Organic Cation Transporters and Organic Anion-Transporting Polypeptides

Jessica E. van Montfoort, Michael Müller, Geny M. M. Groothuis, Dirk K. F. Meijer, Hermann Koepsell and Peter J. Meier
Journal of Pharmacology and Experimental Therapeutics July 1, 2001, 298 (1) 110-115;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Comparison of “Type I” and “Type II” Organic Cation Transport by Organic Cation Transporters and Organic Anion-Transporting Polypeptides

Jessica E. van Montfoort, Michael Müller, Geny M. M. Groothuis, Dirk K. F. Meijer, Hermann Koepsell and Peter J. Meier
Journal of Pharmacology and Experimental Therapeutics July 1, 2001, 298 (1) 110-115;
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