Transcellular passive diffusion

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.]...

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]. 

Most drugs appear to be absorbed in humans by passive diffusion (linear or first-order kinetics). The predominant pathway taken by most drugs is through the epithelial cell, the transcellular route. It is this route that requires the compound to have a reasonable K0/w... 

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). 

Methods for quantifying both the transcellular diffusion and concurrent metabolism of drugs and the unusual transcellular diffusion of membrane-interactive molecules coupled with the influence of protein binding are described in detail. To demonstrate the utility of cultured cell monolayers as a tool for basic science investigations, a subsection is devoted to the elucidation of rate-determining steps and factors in the passive diffusion of peptides across biological membranes. The chapter concludes with a discussion on the judicious use of in vitro cell monolayer results to predict in vivo results. 

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.

Molecules with a large molecular weight or size are confined to the transcellular route and its requirements related to the hydrophobicity of the molecule. The transcellular pathway has been evaluated for many years and is thought to be the main route of absorption of many drugs, both with respect to carrier-mediated transport and passive diffusion. The most well-known requirement for the passive part of this route is hydrophobicity, and a relationship between permeability coefficients across cell monolayers such as the Caco-2 versus log P and log D 7.4 or 6.5 have been established [102, 117]. However, this relationship appears to be nonlinear and reaches a plateau at around log P of 2, while higher lipophilicities result in reduced permeability [102, 117, 118]. Because of this, much more attention has recently been paid towards molecular descriptors other than lipophilicity [86, 119-125] (see section 5.5.6.). The relative contribution between the para-cellular and transcellular components has also been evaluated using Caco-2 cells, and for a variety of compounds with different charges [110, 112] and sizes [112] (see Section 5.4.5). 

This refers to the transport across the epithelial cells, which can occur by passive diffusion, carrier-mediated transport, and/or endocytic processes (e.g., transcytosis). Traditionally, the transcellular route of nasal mucosa has been simply viewed as primarily crossing the lipoidal barrier, in which the absorption of a drug is determined by the magnitude of its partition coefficient and molecular size. However, several investigators have reported the lack of linear correlation between penetrant lipophilicity and permeability [9], which implies that cell membranes of nasal epithelium cannot be regarded as a simple lipoidal barrier. Recently, compounds whose transport could not be fully explained by passive simple diffusion have been investigated to test if they could be utilized as specific substrates for various transporters which have been identified in the... 

The nasal epithelium possesses selective absorption characteristics similar to those of a semipermeable membrane, i.e., it allows a rapid passage of some compounds while preventing the passage of others. The process of transportation across the nasal mucosa involves either passive diffusion, via paracellular or transcellular mechanisms, or occurs via active processes mediated by membrane-bound carriers or membrane-derived vesicles involving endo- or transcytosis. 

Permeation of mAbs across the cells or tissues is accomplished by transcellular or paracellular transport, involving the processes of diffusion, convection, and cellular uptake. Due to their physico-chemical properties, the extent of passive diffusion of classical mAbs across cell membranes in transcellular transport is minimal. Convection as the transport of molecules within a fluid movement is the major means of paracellular passage. The driving forces of the moving fluid containing mAbs from (1) the blood to the interstitial space of tissue or (2) the interstitial space to the blood via the lymphatic system, are gradients in hydrostatic pressure and/or osmotic pressure. In addition, the size and nature of the paracellular pores determine the rate and extent of paracellular transport. The pores of the lymphatic system are larger than those in the vascular endothelium. Convection is also affected by tortuosity, which is a measure of hindrance posed to the diffusion process, and defined as the additional distance a molecule must travel in a particular human fluid (i. e., in vivo) compared to an aqueous solution (i. e., in vitro). 

Nutrients and drugs are absorbed at the intestinal epithelia via several pathways, as illustrated in Fig. 3.1. Depending on their physicochemical properties, including molecular weight, lipophilicity, and hydrogen-binding potential, molecules may pass the intestinal barrier by transcellular or paracellular passive diffusion (Fig. 3.1 A and C). 

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