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Modulation of the Tight Junctions of the Caco-2 Cell Monolayers by H2-antagonists

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Abstract

Purpose. The tight junctions in the intestinal epithelium represent highly specialized intercellular junctions. Ranitidine, an H2-antagonist, causes a tightening of the tight junctions. Hence, we have investigated the effect of ranitidine and other H2-antagonists on the function of the intestinal tight junctions.

Methods. Effect of the H2-antagonists on the tight junctions has been investigated using the transepithelial electrical resistance (TEER) and the transport of mannitol across the Caco-2 cell monolayers.

Results. Four different H2-antagonists caused an increase in the TEER across the Caco-2 cell monolayers, accompanied by a decrease in the permeability for mannitol. The effect was concentration-dependent and saturable. Ranitidine and famotidine, caused a decrease in their own transport rate across the Caco-2 cells. Ranitidine competitively inhibited the increase in TEER caused by famotidine, whereas compounds which represent molecular fragments of ranitidine had no effect. The relative potency of the four H2-antagonists in causing an increase in the TEER correlated inversely with the oral bioavailability of these compounds in humans.

Conclusions. We hypothesize that the H2-antagonists exert their effect on the tight junctions of Caco-2 cells by modulation of interactions among proteins associated with the tight junctional complex.

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Author notes

  1. Liang-Shang L. Gan

    Present address: Department of Drug Metabolism and Pharmacokietics, DuPont Merck Pharmaceutical Co., Newark, Delaware, 19714

  2. Souzan Yanni

    Present address: Sphinx Pharmaceuticals, Inc., Durham, North Carolina, 27707

Authors and Affiliations

  1. Department of Drug Metabolism, Glaxo Inc., Research Triangle Park, North Carolina, 27709

    Liang-Shang L. Gan, Souzan Yanni & Dhiren R. Thakker

  2. Pharmaceutics Division, School of Pharmacy, The University of North Carolina at Chapel Hill, CB#7360, Beard Hall, Chapel Hill, North Carolina, 27599-7360

    Dhiren R. Thakker

Authors
  1. Liang-Shang L. Gan
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  2. Souzan Yanni
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  3. Dhiren R. Thakker
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Gan, LS.L., Yanni, S. & Thakker, D.R. Modulation of the Tight Junctions of the Caco-2 Cell Monolayers by H2-antagonists. Pharm Res 15, 53–57 (1998). https://doi.org/10.1023/A:1011944602662

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  • DOI: https://doi.org/10.1023/A:1011944602662

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