2005 Volume 28 Issue 7 Pages 1249-1253
Although substances, which can increase the paracellular permeability of intestinal mucosa, could be very helpful for increasing the bioavailability of hydrophilic drugs, they are not used therapeutically due to the possibilities of acute or long-term toxicity (intestinal inflammations due to penetration of bacterial fragments into subepithelial spaces). In this paper the abilities of a calcium chelator EDTA and clodronate (a first generation bisphosphonate) to increase the paracellular permeability were assessed using rat jejunum in side-by-side diffusion chambers while the viability of the tissue was monitored by transepithelial potential difference. Although clodronate is less potent than EDTA in depleting calcium from the intestinal tissue, it significantly increased the paracellular permeability of viable rat jejunum “in vitro” when tested at 15 mM and higher concentrations (the highest therapeutic dose dissolved in 250 ml gives a 22 mM solution of clodronate). This effect was reversible under “high-calcium” conditions. Since clodronate therapy does not have any long-term consequences it was concluded that a safe, transient increase of small intestinal permeability is possible. However, the acute gastrointestinal undesired effects, which can develop during the therapy with high doses of clodronate, might also occur after oral applications of paracellular permeability enhancers. Namely, 30 mM and higher concentrations of clodronate caused a loss of the tissue viability in all rat jejunal segments tested in “in vitro” conditions. A similar effect was observed with much lower concentrations of EDTA.
