Evaluation of intestinal absorption and mucosal toxicity using two promoters. II. Rat instillation and perfusion studies

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 (100 mM) and melittin (50 μM) significantly increased absorption of FITC-dextran-4 kDa (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 (50 mM) and melittin (50 μM) 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.