Diffusion paracellular

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-... 

Although different opinions exist about the mechanism of strontium transport through the intestinal wall, the available data suggest that, in contrast to calcium, strontium is absorbed entirely via passive diffusion (= paracellular transport) [27-29]. In vitro [26] and in vivo experiments [30,31] have demonstrated that strontium is always absorbed to a lower extent than calcium, strontium/calcium ratios being approximately 0.45 0.50 [12,31]. The fraction absorbed from dietary intake was calculated to be 20% [32]. 

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. 

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]. 

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. 

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). 

Figure 1 General pathways through which molecules can actively or passively cross a monolayer of cells. (A) Endocytosis of solutes and fusion of the membrane vesicle with the opposite plasma membrane in an active process called transcytosis. (B) Similar to A, but the solute associates with the membrane via specific (e.g., receptor) or nonspecific (e.g., charge) interactions. (C) Passive diffusion between the cells through the paracellular space. (C, C") Passive diffusion (C ) through the cell membranes and cytoplasm or (C") via partitioning into and lateral diffusion within the cell membrane. (D) Active or carrier-mediated transport of an otherwise poorly membrane permeable solute into and/or out of a cellular barrier.

While both paracellular and passive transcellular pathways are available to a solute, the relative contribution of each to the observed transport will depend on the properties of the solute and the membrane in question. Generally, polar membrane-impermeant molecules diffuse through the paracellular route, which is dominated by tight junctions (Section III.A). Exceptions include molecules that are actively transported across one or both membrane domains of a polarized cell (Fig. 2). The tight junction provides a rate-limiting barrier for many ions, small molecules, and macromolecules depending on the shape, size, and charge of the solute and the selectivity and dimensions of the pathway. 

It is assumed that the convective flow of water across the ABL, cell mono-layer, and filter owing to pressure gradients is negligible and that the cell mono-layer is uniformly confluent. When these conditions are not met, Katz and Schaeffer (1991) and Schaeffer et al. (1992) point out that mass transfer resistances of the ABL and filter [as described in Eq. (21)] cannot be used simply without exaggerating the permeability of the cell monolayer, particularly the paracellular route. An additional diffusion cell design was described by Imanidis et al. (1996). 

The paracellular route is the pathway of diffusion of a permeant between cells growing in a monolayer. The ability of solutes to move through this space is... 

Figure 8 Appearance kinetics of radiolabeled solutes that diffuse across Caco-2 cell monolayers via the paracellular pathway. The Transwell system consisted of a donor and receiver solution at pH 7.4. Stirring by planar rotation up to 100 rpm had no effect. The insert with filter, cell monolayer, and donor were transferred to a new receiver chamber at time intervals to maintain sink conditions.

Figure 10 Paracellular permeability of charged solutes as a consequence of their molecular radius illustrates the mechanism of molecular restricted diffusion across negatively charged pores. Solid line depicts the curve drawn through the permeability coefficients of neutral solutes, and the neutral image of positively and negatively charged permeants.

Figure 24 Schematic model of passive diffusion of molecular species of a weak base through the transcellular and paracellular routes of a cell monolayer cultured on a filter support.

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.

Here, Pe takes into account the aqueous boundary layers (/W), transcellular diffusion with metabolism, the paracellular pathway (Pparaceu), and the filter support (PF). It is assumed that drug diffusing through the paracellular route escapes metabolism and contributes insignificantly to the appearance of intact drug in the receiver. 

Adson A, TJ Raub, PS Burton, CL Barsuhn, AR Hilgers, KL Audus, NFH Ho. (1994). Quantitative approaches to delineate paracellular diffusion in cultured epithelial cell monolayers. J Pharm Sci 83 1529-1536. 

Knipp GT, NFH Ho, CL Barsuhn, RT Borchardt. (1997). Paracellular diffusion in Caco-2 cell monolayers Effect of perturbation on the transport of hydrophilic compounds that vary in charge and size. J Pharm Sci 86 1105-1110. 

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