Permeability intestinal epithelium

Walter,E. Janich, S. Roessler, B.J. Hilfinger,J.M. Amidon, G. L., HT29-MTX/Caco-2 cocultures as an in vitro model for the intestinal epithelium In vitro-in vivo correlation with permeability data from rats and humans, J. Pharm. Sci. 85, 1070-1076 (1996). 

Fihn, B. M., A. Sjoqvist, and M. Jodal. Permeability of the rat small intestinal epithelium along the villus-crypt axis effects of glucose transport, Gastroenterology 2000, 119, 1029-1036... 

Culture protocols have been published which describes an accelerated differentiation process where monolayers are ready to be used after 3-7 days of culture [90-92]. One of these systems, the so-called BD BioCoat Intestinal Epithelium Differentiation Environment, is commercially available through BD Bioscience. This system is described to produce monolayers of a quality that are comparable with the typical Caco-2 cells with respect to permeability for drugs transported transcellularly. The paracellular barrier function is however low, as indicated by high mannitol permeability and low TER. The functional capacity for active uptake and efflux is not as thoroughly characterized as for the standard Caco-2 mono-layers. 

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... 

Banan A, Zhang LJ, Shaikh M, Fields JZ, Farhadi A, and Keshavarzian A [2004] Theta-isoform of PKC is required for alterations in cytoskeletal dynamics and barrier permeability in intestinal epithelium a novel function for PKC-theta. Am J Physiol 287 C218-C234... 

Cell monolayers grown on permeable culture inserts form confluent mono-layers with barrier properties and can be used for drug absorption experiments. The most well-known cell line for the in vitro determination of intestinal drug permeability is the human colon adenocarcinoma Caco-2 [20, 21], The utility of the Caco-2 cell line is due to its spontaneous differentiation to enterocytes under conventional cell culture conditions upon reaching confluency on a porous membrane to resemble the intestinal epithelium. This cell model displays small intestinal carriers, brush borders, villous cell model, tight junctions, and high resistance [22], Caco-2 cells express active transport systems, brush border enzymes, and phase I and II enzymes [22-24], Permeability models... 

Other cell lines used in permeability studies include the T84 human colonic adenocarcinoma colonic crypt cell model. This line has a reduced carrier expression, secrets mucus, and has very high resistance [31, 32], The IEC cell line is a rat fetal intestinal epithelium cell with higher permeabilities than Caco-2 cells [33], LLC PKi is a pig kidney epithelial cell line with low expression of efflux systems, but expression systems for transport proteins [32], 2/4/A1 cells are a conditionally immortalized rat fetal intestinal epithelium line with crypt cell-like morphology and temperature-sensitive differentiation [34], They form differentiated monolayers with tight junctions, increased brush border enzymes when grown on extracellular matrices with laminin. Transport of drugs with LP in 2/4/A1 monolayers was comparable to that in the human jejunum and up to 300 times faster than that in Caco-2 monolayers. In contrast, the permeability of HP drugs was comparable in both cell lines [34],... 

Ballard, S.T., J.H. Hunter, and A.E. Taylor. 1995. Regulation of tight-junction permeability during nutrient absorption across the intestinal epithelium. Ann Rev Nutr 15 35. 

Abstract This chapter attempts to give an overview on the properties of the intestinal epithelium with regard to both, barriers to transcellular (transporter and efflux systems) and paracellular (tight junctional complex) drug absorption and transport systems and tight junction modulation. A short introduction into the relation between the innate immune system and modulation of paracellular permeability is equally given. 

Karlsson J, Artursson P (1992) A new diffusion chamber system for the determination of drug permeability coefficients across the human intestinal epithelium that are independent of the unstirred water layer. Biochim Biophys Acta 1111(2) 204—210... 

The second major obstacle of the oral delivery of proteins is the low permeability of proteins in the intestinal epithelium. The uptake of proteins is mediated by passive diffusion across the enterocytes (transcellular diffusion), paracellular diffusion (through intercellular spaces) and mostly by transcytosis (facilitated by receptor-mediated endocytosis). Erodible microcapsules and nanoparticles were shown to be absorbed intact through the GI tract and have opened the pos-... 

Systemic bioavailability is the product of fraction of dose absorbed (/a), fraction of dose escaping gut metabolism (/g), and fraction of dose escaping first-pass metabolism (F ). Permeability class is based upon /a, which may be estimated either in vivo or in vitro by direct measurement of mass transfer across human intestinal epithelium. In vivo methods include (i) mass balance studies using unlabeled, stable-isotope labeled, or a radiolabeled drug substance (ii) oral bioavailability using a reference intravenous dose or (iii) intestinal perfusion studies either in humans or an acceptable animal model. Suitable in vitro methods involve the use of either excised human/animal intestinal tissues or cultured epithelial monolayers. All of these methods are deemed appropriate for drugs whose absorption is controlled by passive mechanisms. 

Effervescence may produce physiological changes within the body. Carbon dioxide bubbling directly onto the intestinal epithelium induced enhanced drug permeability due to an alteration of the paracellular pathway. This, in addition to fluid flow and membrane hydrophobicity concepts, may account for observed increases in drug flux. " ... 

Mariadason, J. M., Barkla, D. H., and Gibson, P. R. (1997). Effect of short-chain fatty acids on paracellular permeability in caco-2 intestinal epithelium model. Am. J. Physiol. 272, G705-G712. 

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