Diffusion paracellular passive

Enterocytes are connected by negatively charged tight junctions, and the intracellular space formed is considered to be the paracellular route [59, 60], The available surface area for paracellular intestinal absorption has been estimated to be about 0.01% of the total surface area of the small intestine [59, 60], The quantitative importance of the paracellular route for macroscopic intestinal absorption of hydrophilic compounds 

194 9 In Vivo Permeability Studies in the Gastrointestinal Tract of Humans 

3A4 in the human enterocyte. Both the parent drug and its metabolite, R/S-norverapamil, can be transported into the blood or back into the intestinal lumen. 

---

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]. 

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). 

A - transcellular passive diffusion B - carrier mediated transport C - transcellular diffusion by endocytosis D - paracellular passive diffusion E - transcellular diffusion by lipid particles F - paracellular passive diffusion via modulation of T.J. 

Figure 1 Pathways of the intestinal barrier. A paracellular passive diffusion, B transcellular passive diffusion, CF influx/efflux facilitated transport facilitated by membrane proteins, G transcytosis, and H endocytosis (reprinted from Reference 2 with kind permission from Dr. Jon Vabeno and Dr. Roy...

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.

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.

Fig. 15.2. Physicochemical molecular descriptors affect the transport route utilised across the intestinal epithelium. To passively diffuse through the membrane (1), the compound (here illustrated with testosterone) should preferably be small, with a molecular weight <500 Da, as well as uncharged and fairly lipophilic. However, compounds that are too lipophilic can stick to the membrane and will not pass through the cells. The paracellular route (2), here exemplified with mannitol, is mainly utilised by smaller (Mw < 200 Da)...

Although the absence of paracellular transport across the BBB impedes the entry of small hydrophilic compounds into the brain, low-molecular-weight lipophilic substances may pass through the endothelial cell membranes and cytosol by passive diffusion [7]. While this physical barrier cannot protect the brain against chemicals, the metabolic barrier formed by the enzymes from the endothelial cell cytosol may transform these chemicals. Compounds transported through the BBB by carrier-mediated systems may also be metabolized. Thus, l-DOPA is transported through the BBB and then decarboxylated to dopamine by the aromatic amino acid decarboxylase [7]. 

Passive diffusion is considered to be the major pathway by which xenobiotics cross the placenta. Paracellular diffusion was shown to be the predominant pathway for transfer of hydrophilic solutes, such as chloride ions across perfused placental lobes and opioid peptides and dextrans across BeWo cells [11-13], It has been proposed that denudations in the syncytiotrophoblasts-containing fibrinoid deposits provide a possible paracellular route across the placenta [14], Transtrophoblast channels in the syncytiotrophoblasts could also be responsible for this mode of diffusion [15], For more lipophilic solutes, the transplacental route appears to be the preferred mode of passage... 

A high concentration of Ca in the intestinal lumen relative to the ECF tends to drive Ca absorption via the paracellular route. Water naturally seeps through the "microspaces (Wasserman, 2004), or cellular jimctions between adjacent enterocytes, during absorption thus creating a paracellular pathway between which 8-30% of the total Ca absorbed (McCormick, 2002) is entrained as a solute. The transfer of Ca by a solvent drag-induced mechanism is via a passive diffusion process in response to increases in the osmolarity of the lumenal contents. This pathway is not site specific and the opportunity for Ca absorption via this route occurs throughout the entire length of the small intestine (Weaver and Liebman, 2002). 

---