Caco paracellular route

To estimate the relative importance of the tight junction and the lateral space composing the paracellular route, let us consider the permeability of mannitol across Caco-2 and MDCK cell monolayers. The results taken from earlier examples are presented below ... 

Figure 27 Relative contributions of the transcellular and paracellular routes for diffusion of the neutral and charged molecular species of (3-blockers across Caco-2 cell mono-layers. APL, alprenolol ATL, atenolol PDL, pindolol PPL, propranolol.

Ilium and coworkers (1994) reported at first that chitosan is able to promote the transmucosal absorption of small polar molecules as well as peptide and protein drugs across nasal epithelia. Immediately afterwards Artursson and collaborators (1994) reported that chitosan can increase the paracellular permeability of [14C]mannitol (a marker for the paracellular route) across Caco-2 intestinal epithelia. 

In Caco-2 cell culture studies chitosan opened transiently the tight junctions between cells, which enables hydrophilic drug to pass through the membrane by the paracellular route [2]. 

The paracellular route is probably less significant in the transport of nanospheres as compared to the transcellular route Tlie tight junctions in between the cells may not allow nanospheres to cross the intestinal epithelial barrier via paracellular route. The transcellular route could allow a restricted passage of the nanospheres across the intestinal mucosal layer because of their moderate size range. In a tissue culture model using Caco-2 (enterocytes) cell monolayers, we have demonstrated transport of PLGA nanospheres across the cells. 

Walter E, Kissel T (1995) Transport of peptidomimetic renin inhibitors across monolayers of a human intestinal cell line (Caco-2) Evidence for self-enhancement of paracellular transport route. J Pharm Sci 3 215-230. 

Prognosis of a compounds permeability should be made stressing limitations of the model. There is no bioavailability prognosis from in vitro data - a cellular assay can provide only permeability potential through a biological membrane. The membrane, in most cases CACO-2 cells, is very similar to what we observe in vivo in the small intestine and resembles many characteristics to in vivo enterocytes. CACO-2 cells can be used for prediction of different pathways across intestinal cells. Best correlation occurs for passive transcellular route of diffusion. Passive paracellular pathway is less permeable in CACO-2 and correlations are rather qualitative than quantitative for that pathway. CACO-2 cells are an accepted model for identification of compounds with permeability problems, for ranking of compounds and selection of best compounds within a series. Carrier-mediated transport can be studied as well using careful characterization of transporters in the cell batch or clone as a prerequisite for transporter studies. 

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