Figure 2.7 Schematic of the apical phospholipid bilayer surface of the epithelial cells, indicating three types of passive diffusion: transcellular (la—>lb—>lc), 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., Curt: Topics Med. Chem., 1, 277-351 (2001). Reproduced with permission from Bentham Science Publishers, Ltd.]

in maintaining the polar distribution of the surface constituents [63]. After a per-meant passes through the cell barrier, it encounters a charge-selective barrier in the basement membrane (Fig. 2.5) [76]. Positively charged drugs have a slightly higher permeability through it. After this barrier, drug molecules may enter the blood capillary network through openings in the highly fenestrated capillaries. Epithelial cell surfaces are composed of bilayers made with phospholipids, as shown in the highly stylized drawing in Fig. 2.7.

Two principal routes of passive diffusion are recognized: transcellular (1a ! 1b ! 1c 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), will be hypothesized as a possible mode of transport for polar or charged amphiphilic molecules.

In the transport across a phospholipid bilayer by passive diffusion, the permeability of the neutral form of a molecule is ^108 times greater than that of the charged form. For the epithelium, the discrimination factor is 105. The basement membrane (Fig. 2.5) allows passage of uncharged molecules more readily than charged species by a factor of 10 [76].

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