INVITRO EFFECTS OF LONG-CHAIN ACYLCARNITINES ON THE PERMEABILITY, TRANSEPITHELIAL ELECTRICAL-RESISTANCE AND MORPHOLOGY OF RAT COLONIC MUCOSA

Absorption-enhancing properties of the long-chain acylcarnitines (C-12 -C18) were examined in vitro utilizing a modified Sweetana-Grass diffu sion cell system. Transepithelial electrical resistance (TEER) and dru g permeability (P) of rat colonic mucosa were used as parameters to de termine the potency, selectivity and reversibility of acylcarnitine-en hancing effects. All long-chain acylcarnitines induced a rapid, concen tration-dependent decrease in mucosal TEER. The minimum or threshold c oncentration (C(t)) which produced a rapid decrease in mucosal TEER wa s determined for each acylcarnitine. Tissues treated with either palmi toyl or lauroyl carnitine at their C, showed significantly better reco very of TEER after removal of the enhancers from the diffusion cells a s compared to the other long-chain acylcarnitines. In addition, palmit oyl and lauroyl carnitine treatment significantly enhanced the mucosal permeability to small, hydrophilic markers without adversely altering tissue morphology. Following enhancer replacement with buffer alone a nd the subsequent recovery of TEER, mucosal permeability was observed to return to near control levels. At higher concentrations of palmitoy l and lauroyl (5 x C(t)), P increased nearly 2-fold over that observed at the C(t); however, epithelial barrier morphology was compromised. This study shows that colonic mucosal tissue mounted in modified Sweet ana-Grass diffusion cells may be a useful model for examining the mech anism(s) of absorption enhancer activity. Moreover, the results presen t evidence that the long-chain acylcarnitines may enhance drug absorpt ion via two different concentration-dependent pathways.