Intestine, selective permeability

In situ perfusion studies assess absorption as lumenal clearance or membrane permeability and provide for isolation of solute transport at the level of the intestinal tissue. Controlled input of drug concentration, perfusion pH, osmolality, composition, and flow rate combined with intestinal region selection allow for separation of aqueous resistance and water transport effects on solute tissue permeation. This system provides for solute sampling from GI lumenal and plasma (mesenteric and systemic) compartments. A sensitive assay can separate metabolic from transport contributions. 

In Section III, emphasis was placed on flux kinetics across the cultured monolayer-filter support system where the passage of hydrophilic molecular species differing in molecular size and charge by the paracellular route was transmonolayer-controlled. In this situation, the mass transport barriers of the ABLs on the donor and receiver sides of the Transwell inserts were inconsequential, as evidenced by the lack of stirring effects on the flux kinetics. In this present section, the objective is to give quantitative insights into the permeability of the ABL as a function of hydrodynamic conditions imposed by stirring. The objective is accomplished with selected corticosteroid permeants which have been useful in rat intestinal absorption studies to demonstrate the interplay of membrane and ABL diffusional kinetics (Ho et al., 1977 Komiya et al., 1980). 

Madara JL, D Barenberg, S Carlsson. (1986). Effects of cytochalasin D on occluding junctions of intestinal absorptive cells Further evidence that the cytoskeleton may influence paracellular permeability and junctional charge selectivity. J Cell Biol 102 2125-2136. 

Artursson, P., Ungell, A.-L., Lofroth, J.-E., Selective paracellular permeability in two models of intestinal absorption cultured monolayers of human intestinal epithelial cells and rat intestinal segments, Pharm. Res. 1993, 30, 1123-1129. 

Thus, the apparent membrane permeability characteristics of hydrophilic compounds listed in Table 3.4 indicate that colonic epithelium is different from small intestinal epithelium in selectivity, or size or density distribution of the paracellular pathway. This is further complicated because of the possible involvement of unidentified carriers or channels for some compounds, as suggested for glycerol and D-xylose. However, the colon-to-SI ratios of the apparent membrane permeability are generally comparable with (or lower than) those calculated considering the morphological surface area, suggesting that such factors are not in favor for colonic absorption in most cases. Matching... 

Despite the availability of other cell lines, Caco-2 cells remain the most widely used intestinal cell culture model at present. This model has provided valuable information necessary for lead optimization in the drug discovery process. However, it is important to understand that compounds with high permeability in this model are typically well absorbed, whereas compounds with low solubility and low permeability in this model may not necessarily be poorly absorbed in vivo. Although this type of positive selection limits the usefulness in providing a structure-permeability relationship, the Caco-2 model has the most effect in drug discovery when the screen is implemented early and in conjunction with other types of in vitro and in vivo permeability/absorption screens. 

This permeability barrier shows selectivity in that small hydrophobic molecules can partition into and diffuse across the lipid bilayer of the cell membrane, whereas small hydrophilic molecules can only diffuse between cells (i.e., through the intercellular junctions). In addition, the presence of uptake and efflux transporters complicates our ability to predict intestinal permeability based on physicochemical properties alone because transporters may increase or decrease absorptive flux. The complexity of the permeability process makes it difficult to elucidate permeability pathways in complex biological model systems such as animals and tissues. For this reason, cultured cells in general, and Caco-2 cells in particular, have been used extensively to investigate the role of specific permeability pathways in drug absorption. 

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