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Journal of Pharmacology and Experimental Therapeutics

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Flavonoids with Epidermal Growth Factor-Receptor Tyrosine Kinase Inhibitory Activity Stimulate PEPT1-Mediated Cefixime Uptake into Human Intestinal Epithelial Cells

Uwe Wenzel, Sabine Kuntz and Hannelore Daniel
Journal of Pharmacology and Experimental Therapeutics October 2001, 299 (1) 351-357;
Uwe Wenzel
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Sabine Kuntz
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Hannelore Daniel
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Abstract

We have tested 33 flavonoids, occurring ubiquitously in foods of plant origin, for their ability to alter the transport of the β-lactam antibiotic cefixime via the H+-coupled intestinal peptide transporter PEPT1 in the human intestinal epithelial cell line Caco-2. Of the flavonoids tested, quercetin, genistein, naringin, diosmin, acacetin, and chrysin increased uptake of [14C]cefixime dose dependently by up to 60%. All other flavonoids were either without effect or decreased the absorption of cefixime. Quercetin was shown to increase the Vmax of cefixime influx without changing the apparent Km for transport. However, the expected concomitant increase in intracellular acidification due to PEPT1-mediated cefixime/H+-cotransport was less pronounced in the presence of quercetin. This suggested that pH regulatory systems such as apical Na+/H+-exchange could be activated by quercetin and maintain the proton-motive driving force for cefixime uptake. Since quercetin and genistein have been shown to inhibit epidermal growth factor (EGF)-receptor tyrosine kinases, we applied tyrphostin 25 to prove whether such an inhibition could explain the stimulatory effects seen on cefixime uptake. It was found that tyrphostin 25 simulated the effects of quercetin by increasing cefixime absorption due to maintenance of the transmembrane pH gradient. In conclusion, our studies show that flavonoids with EGF-receptor tyrosine kinase inhibitory activities enhance the intestinal absorption of the β-lactam antibiotic cefixime in Caco-2 cells by activation of apical Na+/H+-exchange and a concomitant increase of the driving force for PEPT1.

Footnotes

  • This study was supported by Klinge-Pharma (Munich, Germany) and Fujisawa (Osaka, Japan).

  • Abbreviations:
    pHin
    intracellular pH
    BCECF
    2′,7′-bis-(2-carboxyethyl)-5-(and 6)-carboxyfluorescein
    EGFR
    epidermal growth factor receptor
    PTK
    protein tyrosine kinase
    NHE
    Na+/H+-exchange
    • Received April 30, 2001.
    • Accepted July 5, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 299 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 299, Issue 1
1 Oct 2001
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Flavonoids with Epidermal Growth Factor-Receptor Tyrosine Kinase Inhibitory Activity Stimulate PEPT1-Mediated Cefixime Uptake into Human Intestinal Epithelial Cells

Uwe Wenzel, Sabine Kuntz and Hannelore Daniel
Journal of Pharmacology and Experimental Therapeutics October 1, 2001, 299 (1) 351-357;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Flavonoids with Epidermal Growth Factor-Receptor Tyrosine Kinase Inhibitory Activity Stimulate PEPT1-Mediated Cefixime Uptake into Human Intestinal Epithelial Cells

Uwe Wenzel, Sabine Kuntz and Hannelore Daniel
Journal of Pharmacology and Experimental Therapeutics October 1, 2001, 299 (1) 351-357;
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