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Abstract: We compared the effectiveness of two absorption promoters, sodium caprate (C10) and melittin, in increasing the bioavailability (F) of poorly absorbed paracellular flux markers across the intestinal mucosae of rats in situ, together with examination of their effects on morphology. C10 (100mM) and melittin (50μM) significantly increased absorption of FITC-dextran-4kDa (FD4) following jejunal and colonic instillations. F of FD4 following jejunal instillations with C10 was increased from 0.07% to 2.3%, while it was increased from 0.07% to 0.53% in the presence of melittin. F of FD4 following colonic instillations with C10 was increased from 1% to 33% while melittin increased it from 1% to 7%. F of FD70 was unchanged in colonic instillations in the presence of either of the two agents, indicating size limitations of the permeability enhancement effects. In rat jejunal perfusions, C10 (50mM) and melittin (50μM) significantly increased [14C]-mannitol permeability by 9- and 1.9-fold respectively. C10 was more effective than melittin in increasing fluxes in all models. Histology of intestinal sections exposed to either promoter showed mild mucosal damage at those concentrations effective at promoting absorption. Electron microscopy revealed epithelial cell damage induced by both enhancers accompanied by truncation of microvilli, and sloughing. Overall, both melittin and C10 improved bioavailability of polar sugars across the jejunum and colon of rats in situ, which was associated with some degree of mucosal damage. [Copyright &y& Elsevier]

Abstract: 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 (10mM) and melittin (10–50μM) rapidly reduced the transepithelial electrical resistance (TEER) and increased the apparent permeability coefficient (Papp) of [14C]-mannitol and FITC-dextran-4kDa (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 (0.18–70kDa) 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 (0.1–10μM). 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. [Copyright &y& Elsevier]