Evaluation of intestinal absorption enhancement and local mucosal toxicity of two promoters. I. Studies in isolated rat and human colonic mucosae

The effects of two absorption promoters, (sodium caprate (C10) and melittin), on intestinal permeability and viability were measured in intact rat and human colonic epithelia mounted in Ussing chambers. Apical-side addition of C10 (10 mM) and melittin (10–50 μM) rapidly reduced the transepithelial electrical resistance (TEER) and increased the apparent permeability coefficient (Papp) of [14C]-mannitol and FITC-dextran-4 kDa (FD4) across colonic mucosae from both species. Effects of C10 on flux were greater than those of melittin at the concentrations selected. C10 irreversibly decreased TEER, but the effects of melittin were partially reversible. Enhanced permeability of polar sugars (0.18–70 kDa) in colonic mucosae with C10 was accompanied by significant release of lactate dehydrogenase (LDH) from the luminal surface as well as by inhibition of electrogenic chloride secretion induced by the muscarinic agonist, carbachol (0.1–10 μM). Although melittin did not alter electrogenic chloride secretion in rat or human colonic mucosae, it caused leakage of LDH from rat tissue. Gross histology and electron microscopy of rat and human colonic mucosae demonstrated that each permeation enhancer can induce colonic epithelial damage at concentrations required to increase marker fluxes. C10 led to more significant mucosal damage than melittin, characterised by sloughing and mucosal erosion. Overall, these results indicate that while C10 and melittin increase transport of paracellular flux markers across isolated human and rat colonic mucosae in vitro, these effects are associated with some cytotoxicity.