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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Kinetic and Selectivity Differences between Rodent, Rabbit, and Human Organic Cation Transporters (OCT1)

Mark J. Dresser, Andrew T. Gray and Kathleen M. Giacomini
Journal of Pharmacology and Experimental Therapeutics March 2000, 292 (3) 1146-1152;
Mark J. Dresser
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Andrew T. Gray
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Kathleen M. Giacomini
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Abstract

Organic cation transporters play an important role in the absorption, distribution, and elimination of clinical agents, toxic substances, and endogenous compounds. In kidney preparations, significant differences in functional characteristics of organic cation transport between various species have been reported. However, the underlying molecular mechanisms responsible for these interspecies differences are not known. The goal of this study was to determine the kinetics and substrate selectivities of organic cation transporter (OCT1) homologs from mouse, rat, rabbit, and human that may contribute to interspecies differences in the renal and hepatic handling of organic cations. With a series of n-tetraalkylammonium (nTAA) compounds, a correlation between increasing alkyl chain length and affinity for the four OCT1 homologs was observed. However, the apparent affinity constants (Ki) differed among the species homologs. For the mouse homolog mOCT1, apparentKi values ranged from 7 μM for tetrabutylammonium to 2000 μM for tetramethylammonium. In contrast, the human homolog hOCT1 exhibited weaker interactions with the nTAA compounds. Trans-stimulation studies and current measurements in voltage-clamped oocytes demonstrated that larger nTAA compounds were transported at greater rates in oocytes expressing hOCT1, whereas smaller nTAAs were transported at greater rates in oocytes expressing mOCT1 or rOCT1. The rabbit homolog rbOCT1 exhibited intermediate properties in its interactions with nTAAs compared with its rodent and human counterparts. This report demonstrates that the human OCT1 homolog has functional properties distinct from those of the rodent and rabbit OCT1 homologs. The study underscores potential difficulties in extrapolating data from preclinical studies in animal models to humans.

Footnotes

  • Send reprint requests to: Kathleen M. Giacomini, Ph.D., Department of Biopharmaceutical Sciences, University of California-San Francisco, 513 Parnassus Ave., Box 0446 S-926, San Francisco, CA 94143-1936. E-mail: kmg{at}itsa.uscf.edu

  • ↵1 This work was supported by a Grant GM36780 from the National Institutes of Health.

  • Abbreviations:
    BLM
    basolateral membrane
    BBM
    brush border membrane
    nTAA
    n-tetraalkylammonium
    OCT
    organic cation transporter
    MPP+
    1-methyl-4-phenylpyridinium
    TMA
    tetramethylammonium
    TEA
    tetraethylammonium
    TPrA
    tetrapropylammonium
    TBA
    tetrabutylammonium
    TPeA
    tetrapentylammonium
    • Received September 3, 1999.
    • Accepted November 10, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 292 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 292, Issue 3
1 Mar 2000
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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Kinetic and Selectivity Differences between Rodent, Rabbit, and Human Organic Cation Transporters (OCT1)

Mark J. Dresser, Andrew T. Gray and Kathleen M. Giacomini
Journal of Pharmacology and Experimental Therapeutics March 1, 2000, 292 (3) 1146-1152;

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Kinetic and Selectivity Differences between Rodent, Rabbit, and Human Organic Cation Transporters (OCT1)

Mark J. Dresser, Andrew T. Gray and Kathleen M. Giacomini
Journal of Pharmacology and Experimental Therapeutics March 1, 2000, 292 (3) 1146-1152;
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