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This report describes the effect of rhamnolipids (RLs) on the tight junctions (TJ) of the intestinal epithelium using the rat in-situ closed loop model.We investigated the transport of 5 (6)-carboxyfluorescein (CF) and fluorescein isothiocyanate-labeled dextrans with average molecular weights of 4.4 and 10 kDa (FD-4 and FD-10) when co-administered with different concentrations of RLs. Lactate dehydrogenase (LDH) leakage assay and histopathological examination of treated intestinal loops were used to assess potential toxicity of RLs. Further, the effect of kaempferol on accelerating the resealing of the tight junctions in vivo was also investigated RESULTS: Data shows that administration of different RLs concentrations (1.0-5.0% v/v) increased CF absorption through rat intestine by 2.84- and 15.82-folds with RLs concentrations of 1.0% and 5.0% v/v, respectively. RLs exhibited size-dependent increase on FD-4 and FD-10 absorption. Dosing RLs at 1.0% v/v didn't cause a significant LDH leakage or histopathological changes to intestinal mucosa compared to higher concentrations, which showed a progressive damaging effect. Using kaempferol, a natural flavonoid that stimulates the assembly of the TJs, proved to enhance the recovery of barrier properties of the intestinal mucosa treated with high concentrations of RLs (2.5% and 5% v/v).These results collectively illustrate the ability of RLs to enhance oral bioavailability of different molecules across the intestinal epithelial membrane in a concentration- and time-dependent fashion.

We have reported that the cell-penetrating peptide (CPP) penetratin acts as a potential absorption enhancer in oral insulin delivery systems and that this action occurs through noncovalent intermolecular interactions. However, the region-dependent role of CPPs in intestinal insulin absorption has not been clarified. To identify the intestinal region where CPPs have the most effect in increasing insulin absorption, the region-dependent action of penetratin was investigated using in situ closed intestinal loops in rats. The order of the insulin area under the insulin concentration–time curve (AUC) increase effect by l-penetratin was ileum > jejunum > duodenum > colon. By contrast, the AUC order after coadministration of insulin with d-penetratin was colon > duodenum ≥ jejunum and ileum. We also compared the effects of the l- and d-forms of penetratin, R8, and PenetraMax on ileal insulin absorption. Along with the CPPs used in this study, l- and d-PenetraMax produced the largest insulin AUCs. An absorption study using ilea pretreated with CPPs showed that PenetraMax had no irreversible effect on the intestinal epithelial membrane. The degradation of insulin in the presence of CPPs was assessed in rat intestinal enzymatic fluid. The half-life (t1/2) of insulin increased from 14.5 to 23.7 and 184.7 min in the presence of l- and d-PenetraMax, respectively. These enzymatic degradation-resistant effects might contribute partly to the increased ileal absorption of insulin induced by d-PenetraMax. In conclusion, this study demonstrated that the ability of the l- and d-forms of penetratin to increase intestinal insulin absorption was maximal in the ileum and the colon, respectively, and that d-PenetraMax is a powerful but transient enhancer of oral insulin absorption.