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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Correlation between Epithelial Cell Permeability of Cephalexin and Expression of Intestinal Oligopeptide Transporter

Xiao-Yan Chu, Gloria P. Sánchez-Castaño, Kazutaka Higaki, Doo-Man Oh, Cheng-Pang Hsu and Gordon L. Amidon
Journal of Pharmacology and Experimental Therapeutics November 2001, 299 (2) 575-582;
Xiao-Yan Chu
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Gloria P. Sánchez-Castaño
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Kazutaka Higaki
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Doo-Man Oh
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Cheng-Pang Hsu
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Gordon L. Amidon
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Abstract

The proton-coupled oligopeptide transporter (PEPT1) has been shown to mediate mucosal cell transport of di- and tripeptide, and some peptidomimetic drugs. In this study, we determined the correlation between PEPT1 protein expression and the permeability of cephalexin, a substrate of PEPT1, in human PEPT1 (hPEPT1)-overexpressed Caco-2 cells (Caco-2/hPEPT1 cells) and rat jejunum. Caco-2/hPEPT1 cells with various levels of hPEPT1 expression were established by an adenoviral transfection system. The effective intestinal permeability (Peff) in rat jejunum was evaluated using a single pass in situ perfusion method. The level of PEPT1 in Caco-2/hPEPT1 cells and rat intestinal mucosal samples was quantitated by densitometry after immunoblotting and enhanced chemiluminescence detection. In Caco-2/hPEPT1 cells, an excellent correlation was observed between cephalexin uptake and hPEPT1 expression (R2 = 0.96, P < 0.005). This demonstrates that cephalexin uptake is directly proportional to hPEPT1 expression. In the rat perfusion study, the mean Peff ± S.D. (n = 15) of cephalexin was 3.89 ± 1.63 × 10−5 cm/s. A very significant correlation between PEPT1 expression and cephalexin permeability with an R2 = 0.63 (P < 0.001) was observed. This indicates that the variation in PEPT1 expression is one of the major factors accounting for variable intestinal cephalexin absorption. To our knowledge, this is the most direct evidence that variation of PEPT1 expression is correlated with absorption permeability variation of peptide-like compounds in vitro and in vivo.

Footnotes

  • This work was supported by National Institutes of Health Grant GM 37188.

  • Abbreviations:
    PEPT1
    proton-coupled oligopeptide transporter
    Caco-2/hPEPT1 cells
    hPEPT1 overexpressed Caco-2 cells
    HPLC
    high-performance liquid chromatography
    Gly-Sar
    glycyl-sarcosine
    PEG 4000
    polyethylene glycol 4000
    m.o.i.
    multiplicity of infection
    pfu
    plaque-forming unit
    MES
    2-(N-morpholino)ethanesulfonic acid
    PAGE
    polyacrylamide gel electrophoresis
    ECL
    enhanced chemiluminescence
    Peff
    effective intestinal permeability
    • Received May 9, 2001.
    • Accepted July 15, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 299 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 299, Issue 2
1 Nov 2001
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Correlation between Epithelial Cell Permeability of Cephalexin and Expression of Intestinal Oligopeptide Transporter

Xiao-Yan Chu, Gloria P. Sánchez-Castaño, Kazutaka Higaki, Doo-Man Oh, Cheng-Pang Hsu and Gordon L. Amidon
Journal of Pharmacology and Experimental Therapeutics November 1, 2001, 299 (2) 575-582;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Correlation between Epithelial Cell Permeability of Cephalexin and Expression of Intestinal Oligopeptide Transporter

Xiao-Yan Chu, Gloria P. Sánchez-Castaño, Kazutaka Higaki, Doo-Man Oh, Cheng-Pang Hsu and Gordon L. Amidon
Journal of Pharmacology and Experimental Therapeutics November 1, 2001, 299 (2) 575-582;
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