Transepithelial permeability

Anderberg, E. K., C. Nystrom, and P. Artursson. Epithelial transport of drugs in cell culture. VII Effects of pharmaceutical surfactant excipients and bile adds on transepithelial permeability in monolayers of human intestinal epithelial (Caco-2) cells,... 

Claude P [1978] Morphological factors influencing transepithelial permeability a model for the resistance of the zonula occludens. 1 Membr Biol 39 219-232... 

Dimitrijevic, D., A. Shaw, and A. Florence. 2000. Effects of some non-ionic surfactants on transepithelial permeability in Caco-2 cells. J Pharm Pharmacol 52 157. 

SaladikDT, Soler AP, Lewis SA, and Mullin JM.Cell Division Does Not Increase Transepithelial Permeability of LLC-PKl Cell Sheets. Experimental Cell Research 220 446-455,1995. 

Anderberg EK, Nystrom C, and Artursson P. Epithelial Transport of Drugs in Cell Culture. VII Effects of Pharmaceutical Surfactant Excipients and Bile Acids on Transepithelial Permeability in Monolayers of Human Intestinal Epithelial (Caco-2) Ce ls. JPharm Sci 1992 81 879-887. 

Dimitrijevic D, ShawT, and Florence AT. Effects of Some Non-Ionic Surfactants on Transepithelial Permeability in Caco-2 cells. J Pharm Pharmacol 2000 52 157-162. 

There are different methods to measure transepithelial permeability in tissues and cell cultures, e.g., the lanthaniun tracer technique, radio-isotope techniques using extracellular tracers and light microscopy techniques with large polar molecules, such as fluorescein isothiocyanate (FITC)-dextrans with an average molecular weight of at least 4 kD, or the use of electrophysiological methods such as TEER measurements. 

In series with a desolvation energy barrier required to disrupt aqueous solute hydrogen bonds [14], the lipid bilayer offers a practically impermeable barrier to hydrophilic solutes. It follows that significant transepithelial transport of water-soluble molecules must be conducted paracellularly or mediated by solute translocation via specific integral membrane proteins (Fig. 6). Transcellular permeability of lipophilic solutes depends on their solubility in GI membrane lipids relative to their aqueous solubility. This lumped parameter, membrane permeability,... 

Figure 14 Observed permeability coefficients of urea and mannitol across monolayers of rat alveolar epithelial cells in primary culture in the Transwell system are correlated with transepithelial electrical resistance and days in culture.

The ex vivo techniques of drug permeability using the Ussing chamber has extensively developed in the last few decades. It is very easy to monitor and therefore to maintain tissue viability throughout the study. This is ensured by monitoring the transepithelial potential difference and short-circuits current... 

The example of amprenavir, an HIV-1 protease inhibitor, shows that intestinal metabolism can also be used as a strategy to enhance the bioavailability of compounds. In the biopharmaceutics classification system (BCS), amprenavir can be categorized as a class II compound it is poorly soluble but highly permeable [51]. Fosamprenavir, the water-soluble phosphate salt of amprenavir, on the other hand, shows poor transepithelial transport. However, after oral administration of fosamprenavir, this compound is metabolized into amprenavir in the intestinal lumen and in the enterocytes mainly by alkaline phosphatases, resulting in an increased intestinal absorption [51, 174],... 

Figure 9.1 Relationship between the transepithelial electrical resistance (TEER) value of the passage-cultured human nasal epithelial cell layer and permeability of 14C-mannitol (o, passage-2 A, passage-3 , passage-4) and budesonide ( , passage-2 , passage-3 , passage-4). (Data from Ref. [40]).

Gorodeski GI, Romero MF, Hopfer U, Rorke E, Utian WH, and Eckert RL [ 1994] Human uterine cervical epithelial cells grown on permeable support—a new model for the study of differentiation and transepithelial transport. Differentiation 56 107-118... 

Baida MS, Whitney JA, Flores C, Gonzalez-Mariscal L, Cereijido M, and Matter K [1996] Functional dissociation of paracellular permeability and transepithelial electrical resistance and disruption of the apical-basolateral intramembrane diffusion barrier by the expression of a mutant tight junction membrane protein. J Cell Biol 134 1031-1049... 

Caco-2 cells have been valuable in the estimation of drug absorption potential, transport mechanisms, and effect of permeation enhancers on transepithelial transport.35,39,53,67-69,78-81 Owing to the sensitivity of the cells and the limited solubility of new molecular entities, Caco-2 permeability studies are routinely done with relatively low concentration of compounds. One way to increase the solubility of these compounds is to use organic solvents. The low tolerability of Caco-2 cells to organic solvents limits the use of this approach in permeability studies. 

The successful application of in vitro models of intestinal drug absorption depends on the ability of the in vitro model to mimic the relevant characteristics of the in vivo biological barrier. Most compounds are absorbed by passive transcellular diffusion. To undergo tran-scellular transport a molecule must cross the lipid bilayer of the apical and basolateral cell membranes. In recent years, there has been a widespread acceptance of a technique, artificial membrane permeation assay (PAMPA), to estimate intestinal permeability.117118 The principle of the PAMPA is that, diffusion across a lipid layer, mimics transepithelial permeation. Experiments are conducted by applying a drug solution on top of a lipid layer covering a filter that separates top (donor) and bottom (receiver) chambers. The rate of drug appearance in the bottom wells should reflect the diffusion across the lipid layer, and by extrapolation, across the epithelial cell layer. 

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