Paracellular

The blood-brain barrier (BBB) forms a physiological barrier between the central nervous system and the blood circulation. It consists of glial cells and a special species of endothelial cells, which form tight junctions between each other thereby inhibiting paracellular transport. In addition, the endothelial cells of the BBB express a variety of ABC-transporters to protect the brain tissue against toxic metabolites and xenobiotics. The BBB is permeable to water, glucose, sodium chloride and non-ionised lipid-soluble molecules but large molecules such as peptides as well as many polar substances do not readily permeate the battier. 

Gum arabic. (GA) modifies paracellular water and electrolyte transport in the small intestine. Digestive Diseases and Sciences, Vol. 48, No.4, (April 2003), pp. 755-760, ISSN 0163-2116. 

Although a portion of the nutrients released from feedstuff s is absorbed by diffusing across the apical membrane of enterocytes or through the junctional complexes of adjacent enterocytes (paracellular absorption), the majority of nutrients are absorbed from the lumen of the GIT by carrier proteins that are inserted into the apical membrane of enterocytes and colonocytes. 

For cellular models, a more compUcated form of the above equation is needed, to factor in paracellular, facilitated uptake and effiux transport, etc. [22].)... 

FIG. 2 Mechanisms of drug transfer in the cellular layers that line different compartments in the body. These mechanisms regulate drug absorption, distribution, and elimination. The figure illustrates these mechanisms in the intestinal wall. (1) Passive transcellular diffusion across the lipid bilayers, (2) paracellular passive diffusion, (3) efflux by P-glycoprotein, (4) metabolism during drug absorption, (5) active transport, and (6) transcytosis [251]. 

PAMPA is typically used to make a prediction of the passive, transcellular absorption of a compound. Compounds which may be absorbed by a paracellular mechanism or may be substrates for active transport (uptake or efflux) are usually better assessed in a cell based system. A combination of assays can be applied to gain a greater understanding of the permeability and transport properties of a compound. 

Fig. 9 Schematic representation depicting the movement of molecules from the absorbing (mucosal or apical) surface of the GIT to the basolateral membrane and from there to blood. (A) transcellular movement through the epithelial cell. (B) Paracellular transport via movement between epithelial cells. (Q Specialized carrier-mediated transport into the epithelial cell. (D) Carrier-mediated efflux transport of drug out of the epithelial cell. (Copyright 2000 Saguaro Technical Press, Inc., used with permission.)...

Y-L He, S Murby, G Warhurst, L Gifford, D Walker, J Ayrton, R Eastmond, M Rowland. Species differences in size discrimination in the paracellular pathway reflected by oral bioavailability of poly (ethylene glycol) and D-peptides. J Pharm Sci 87 626-633, 1998. 

Figure 2.7 Schematic of the apical phospholipid hilayer surface of the epithelial cells, indicating three types of passive diffusion transcellular (la > 1 b 1 c), paracellular (2a >2b 2c), and the hypothesized lateral, under the skin of the tight junction (3a—> 3b—> 3c) modes. Tight-junction matrix of proteins highly stylized, based on Ref. 75. [Avdeef, A., Curr. Topics Med. Chem., 1, 277-351 (2001). Reproduced with permission from Bentham Science Publishers, Ltd.]...

Two principal routes of passive diffusion are recognized transcellular (la —> lb —> lc in Fig. 2.7) and paracellular (2a > 2b > 2c). Lateral exchange of phospholipid components of the inner leaflet of the epithelial bilayer seems possible, mixing simple lipids between the apical and basolateral side. However, whether the membrane lipids in the outer leaflet can diffuse across the tight junction is a point of controversy, and there may be some evidence in favor of it (for some lipids) [63]. In this book, a third passive mechanism, based on lateral diffusion of drug molecules in the outer leaflet of the bilayer (3a > 3b > 3c), wih be hypothesized as a possible mode of transport for polar or charged amphiphilic molecules. 

Anderberg, E. K. Lindmark, T. Artursson, P., Sodium caprate ehcits dilations in human intestinal tight junctions and enhances drug absorption by the paracellular route, Pharm. Res. 10, 857-864 (1993). 

Noach, A. B. J. Enhancement of paracellular drug transport across epithelia—in vitro and in vivo studies, Pharm. World Sci. 17, 58-60 (1995). 

Adson, A. Burton, P. S. Raub, T. J. Barsuhn, C. L. Audus, K. L. Ho, N. F. H., Passive diffusion of weak organic electrolytes across Caco-2 cell monolayers Uncoupling the contributions of hydrodynamic, transcellular, and paracellular barriers, J. Pharm. Sci. 84, 1197-1204 (1995). 

Karlsson, J. Ungell, A.-L. Grasjo, J. Artursson, P., Paracellular drug transport across intestinal epithelia Influence of charge and induced water flux, Eur. J. Pharm. Sci. 9, 47-56 (1999). 

Collett, A. Sims, E. Walker, D. He, Y.-L. Ayrton, J. Rowland, M. Warhurst, G., Comparison of HT29-18-C1 and Caco-2 cell lines as models for studying intestinal paracellular drug absorption, Pharm. Res. 13, 216-221 (1996). 

Theoretical aspects of diffusional resistances are discussed in Part I of this volume. Following these discussions, parallel transcellular and paracellular ... 

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 5 Parallel transcellular and paracellular pathways through intestinal epithelial cell monolayer.

C. Paracellular Transport—Equivalent Pore and Circuit Theory... 

With respect to the size and charge selectivity of paracellular pathways, equivalent pore theory has been utilized to calculate an effective radius based on the membrane transport of uncharged hydrophilic molecules, while equivalent circuit theory has been used to separate mediated from paracellular membrane transport of small ions. The term equivalent should be emphasized, as selectivity parameters are obtained from membrane transport data, so phenomenological information is used to quantitate the magnitude of aqueous pathways... 

Ion transport across membranes can be evaluated by using mucosal and serosal electrodes to read transepithelial current (I) and potential difference OP). With these parameters, equivalent circuit analysis can be utilized to account for the relative contributions of transcellular and paracellular pathways. Ionic flux (J) is defined by the Nernst-Planck equation,... 

Additional epithelial aqueous pathways of significantly smaller radius (<3 A) have also been documented utilizing both equivalent pore and circuit theory [25], These pathways may correspond to specific channels through lipid membranes as opposed to paracellular pathways. Osmotically activated ion channels [35] and even specific water channels [36] have been characterized in renal epithelia. In intestinal epithelia, mucosal chloride channels have been studied in secreting crypt cells, and basolateral potassium channels in colonic epithelia serve cellular ion and volume homeostatic functions. 

V represents the volume of the mucosal compartment and A the surface area of the mucosal barrier. Passive paracellular solute flux is also proportional to mucosal solute concentration, where the proportionality constant is the ratio of the... 

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