In this study we compared the effect of two surfactants (laureth-6 and sodium docusate) on the permeability of a model hydrophilic drug across three different epithelia (Caco-2 cells, stripped porcine jejunum and rat ileo-jejunum). Among the tested epithelia Caco-2 cells are the tightest with the trans-epithelial electrical resistance of 372+/-4 Omega cm2 followed by porcine jejunum (124+/-8 Omega cm2) and rat ileo-jejunum (33+/-2 Omega cm2). Both surfactants decreased the trans-epithelial electrical resistance and increased the permeability of a model drug across Caco-2 cells at concentrations as low as 0.02 mg/ml, with more pronounced effect observed for laureth-6. On the other hand, ten times higher concentrations (0.2 mg/ml) did not affect the permeability of the model drug across the porcine jejunum. Similarly, laureth-6 at this high concentration had no effect on the trans-epithelial electrical resistance of the rat ileo-jejunum and did not increase the permeability of the model drug across this tissue. On the basis of these results we concluded that Caco-2 cells are much more sensitive to the investigated surfactants, that act as permeation enhancers, than the native intestinal tissues. Therefore, the results obtained in the experiments with Caco-2 cells might exaggerate the effects of the surfactants on the permeability compared to in vivo situation.