Modulation of the tight junctions of the Caco-2 cell monolayers by H2-antagonists

Pharm Res. 1998 Jan;15(1):53-7. doi: 10.1023/a:1011944602662.


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.

MeSH terms

  • Biological Availability
  • Caco-2 Cells / drug effects*
  • Caco-2 Cells / physiology
  • Electric Impedance
  • Histamine H2 Antagonists / pharmacokinetics
  • Histamine H2 Antagonists / pharmacology*
  • Humans
  • Membrane Potentials / drug effects
  • Ranitidine / pharmacokinetics
  • Ranitidine / pharmacology*
  • Tight Junctions / drug effects*


  • Histamine H2 Antagonists
  • Ranitidine