Comparison of different intestinal epithelia as models for absorption enhancement studies.

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.

Polarised transport of monocarboxylic acid type drugs across rat jejunum in vitro: the effect of mucolysis and ATP-depletion.

The transport characteristics of monocarboxylic acid type drugs (ketoprofen, ibuprofen and gemfibrozil) across the excised jejunal segments and artificial (octanol impregnated) membrane in side-by-side diffusion cells were studied. All three model drugs permeated faster across the intestinal tissue in the mucosal-to-serosal direction than in the opposite direction. No polarised transport of tested drugs was observed when the mucosal side of the intestine was treated with mucus disrupting agent, L-cysteine 1% (w/v), which significantly increased the microclimate pH at the mucosal surface of the intestine. Similar effects on the transport characteristics of model drugs and microclimate pH were observed when metabolic inhibitor, sodium azide (10mM), was present in the incubation medium. Furthermore, the direction of proton gradient across the artificial membrane was shown to significantly influence the transport of model drugs across this membrane. The results of this study indicate that the inwardly directed proton gradient maintained by the acidic microclimate pH at the intestinal surface could be considered as a driving force for the transport of monocarboxylic acid type drugs across the intestinal epithelia and could explain rapid absorption of these drugs after oral application.