MECHANISMS OF ABSORPTION ENHANCEMENT BY MEDIUM-CHAIN FATTY-ACIDS IN INTESTINAL EPITHELIAL CACO-2 CELL MONOLAYERS

Sodium salts of medium chain fatty acids (MCFAs) enhance the absorptio n of hydrophilic drugs across the intestinal mucosa, but the mechanism behind the effect is largely unknown. In this study, the dose-depende nt effects of the sodium salts of four MCFAs, C6 (caproate), C8 (capry late), C12 (caprate) and C12 (laurate), on the permeability of the hyd rophilic marker molecule ['4C]mannitol were studied in monolayers of t he human intestinal epithelial cell line, Caco-2, grown on permeable s upports. C8, C10 and C12, but not C6, enhanced the permeability of [C- 14]mannitol in a dose-dependent manner. Comparison of the cellular eff ects of the MCFAs at concentrations that gave comparable (8.1- to 8.5- fold) absorption enhancement showed that: 1) C8 was active as absorpti on enhancer only when the tonicity of the medium was increased; 2) abs orption enhancement mediated by C10 was related to a redistribution of the cytoskeleton and structural dilatations in the tight junctions; a nd 3) C12 was without effect on the cytoskeleton and cellular morpholo gy. Studies on C10 under anisotonic conditions showed that deviations from isotonicity enhanced its effect. These results suggest that struc turally similar MCFAs display dramatic differences in their mechanism of action. in addition, the effects of osmolality provide an explanati on for the previously reported variability in the efficacy of MCFAs as absorption enhancers.