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Research ArticleArticle

Monocarboxylate Transporter-Mediated Transport of γ-Hydroxybutyric Acid in Human Intestinal Caco-2 Cells

Wing Ki Lam, Melanie A. Felmlee and Marilyn E. Morris
Drug Metabolism and Disposition March 2010, 38 (3) 441-447; DOI: https://doi.org/10.1124/dmd.109.030775
Wing Ki Lam
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Melanie A. Felmlee
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Marilyn E. Morris
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Abstract

The objectives of this study were to determine mRNA expression of monocarboxylate transporters (MCT) and to evaluate intestinal transport of the MCT substrates γ-hydroxybutyrate (GHB) and d-lactate in human intestinal Caco-2 cells. The presence of mRNA for MCT1, 2, 3, and 4 was observed in Caco-2 cells. The uptake of both GHB and d-lactate in Caco-2 cells was demonstrated to be pH- and concentration-dependent and sodium-independent. The uptake of GHB and d-lactate was best described by a Michaelis-Menten equation with passive diffusion (GHB: Km = 17.6 ± 10.5 mM, Vmax = 17.3 ± 11.7 nmol/min/mg, and P = 0.38 ± 0.15 μl/min/mg; and d-lactate: Km = 6.0 ± 2.9 mM, Vmax = 35.0 ± 18.4 nmol/min/mg, and P = 1.3 ± 0.6 μl/min/mg). The uptake of GHB and d-lactate was significantly decreased by the known MCT inhibitor α-cyano-4-hydroxycinnamate and the MCT substrates GHB and d-lactate but not by the organic cation tetraethylammonium chloride. Directional flux studies with both GHB and d-lactate suggested the involvement of carrier-mediated transport with the permeability in the apical to basolateral direction higher than that in the basolateral to apical direction. These findings confirm the presence of MCT1–4 in Caco-2 cells and demonstrate GHB and d-lactate transport characteristics consistent with proton-dependent MCT-mediated transport.

Footnotes

  • This work was supported in part by the National Institutes of Health National Institute on Drug Abuse [Grant DA023223]. W.K.L. was supported in part by an Undergraduate Summer Fellowship, and M.A.F. was supported by a Graduate Fellowship from Pfizer Global Research and Development.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.109.030775.

  • ABBREVIATIONS:

    MCT
    monocarboxylate transporter
    GHB
    γ-hydroxybutyric acid
    XP13512
    (±)-1-([(α-isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane acetic acid
    CHC
    α-cyano-4-hydroxycinnamate
    TEA
    tetraethylammonium chloride
    MES
    2-(N-morpholino)ethanesulfonic acid
    RT-PCR
    reverse transcriptase-polymerase chain reaction
    AP
    apical
    BL
    basolateral
    SMCT
    sodium-coupled monocarboxylate transporter
    siRNA
    small interfering RNA.

    • Received October 13, 2009.
    • Accepted December 1, 2009.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (3)
Drug Metabolism and Disposition
Vol. 38, Issue 3
1 Mar 2010
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Research ArticleArticle

Monocarboxylate Transporter-Mediated Transport of γ-Hydroxybutyric Acid in Human Intestinal Caco-2 Cells

Wing Ki Lam, Melanie A. Felmlee and Marilyn E. Morris
Drug Metabolism and Disposition March 1, 2010, 38 (3) 441-447; DOI: https://doi.org/10.1124/dmd.109.030775

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Research ArticleArticle

Monocarboxylate Transporter-Mediated Transport of γ-Hydroxybutyric Acid in Human Intestinal Caco-2 Cells

Wing Ki Lam, Melanie A. Felmlee and Marilyn E. Morris
Drug Metabolism and Disposition March 1, 2010, 38 (3) 441-447; DOI: https://doi.org/10.1124/dmd.109.030775
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