Transcellular transport/absorption

Penetration enhancers are low molecular weight compounds that can increase the absorption of poorly absorbed hydrophilic drugs such as peptides and proteins from the nasal, buccal, oral, rectal, and vaginal routes of administration [186], Chelators, bile salts, surfactants, and fatty acids are some examples of penetration enhancers that have been widely tested [186], The precise mechanisms by which these enhancers increase drug penetration are largely unknown. Bile salts, for instance, have been shown to increase the transport of lipophilic cholesterol [187] as well as the pore size of the epithelium [188], indicating enhancement in both transcellular and paracellular transport. Bile salts are known to break down mucus [189], form micelles [190], extract membrane proteins [191], and chelate ions [192], While breakdown of mucus, formation of micelles, and lipid extraction may have contributed predominantly to the bile salt-induced enhancement of transcellular transport, chelation of ions possibly accounts for their effect on the paracellular pathway. In addition to their lack of specificity in enhancing mem-... 

Bourdet DL, Pollack GM, Thakker DR (2006) Intestinal absorptive transport of the hydrophilic cation ranitidine A kinetic modeling approach to elucidate the role of uptake and efflux transporters and paracellular vs. transcellular transport in Caco-2 cells. Pharm Res 23 1178-87. 

The enzymatic degradation of insulin was also shown to occur in the cytosol of alveolar cells, the pH optimum of the proteases being 7.4 [38]. To what extent intracellular proteases play a significant role in limiting the absorption of insulin is not clear, since the size of insulin likely allows paracellular transport over the alveolar epithelium. However, for proteins of higher molecular weight, that require transcellular transport, these proteases might certainly limit bioavailability. 

The most efficient rectal absorption enhancers, which have been studied, include surfactants, bile acids, sodium salicylate (NaSA), medium-chain glycerides (MCG), NaCIO, enamine derivatives, EDTA, and others [45 17]. Transport from the rectal epithelium primarily involves two routes, i.e., the paracellular route and the transcellular route. The paracellular transport mechanism implies that drugs diffuse through a space between epithelial cells. On the other hand, an uptake mechanism which depends on lipophilicity involves a typical transcellular transport route, and active transport for amino acids, carrier-mediated transport for (3-lactam antibiotics and dipeptides, and endocytosis are also involved in the transcellular transport system, but these transporters are unlikely to express in rectum (Figure 8.7). Table 8.3 summarizes the typical absorption enhancers in rectal routes. 

Physical barrier. Following oral administration of macromolecular drugs, their potential absorption pathways from the intestinal lumen to the bloodstream can be classified into transcellular transport associated with adsorptive or receptor-mediated endocytosis and paracellu-lar transport (Fig. 10.1). The GI tract surface consists of a tightly bound single layer of epithelial cells covered with thick and viscous mucus, which serves as a defensive deterrent against permeation of xenobi-otics and harmful pathogens. The epithelial cells in the GI tract are... 

Figure 10.1 Pathways for intestinal absorption of macromolecular drugs, (a) Paracellular transport of macromolecules can be achieved by altering or disrupting the tight junctions that exist between cells and are only permeable to small molecules (<100 to 200 Da). (b) Adsorptive enterocytes and (c) M cells of Peyer s patches allow transcellular transport of macromolecules involving transcytosis and receptor-mediated endocytosis.

Abstract This chapter attempts to give an overview on the properties of the intestinal epithelium with regard to both, barriers to transcellular (transporter and efflux systems) and paracellular (tight junctional complex) drug absorption and transport systems and tight junction modulation. A short introduction into the relation between the innate immune system and modulation of paracellular permeability is equally given. 

Fatty acids increase intestinal absorption via their influence on the paracellular and transcellular transport route. Most interesting results were obtained with lauric acid, palmitic acid, capylic acid, and oleic acid or their salts. Cytotoxic effects of fatty acids are concentration dependent long-chain unsaturated fatty acids especially can cause epithelial cell damage. ° ... 

Absorption barriers are related to the permeability of drug molecules across the gastrointestinal membrane including the colonic membrane. There are two distinct mechanisms for molecules to cross the membrane via paracellular transport and transcellular transport (Fig. 5). Para-cellular transport involves only passive diffusion where the molecules pass through the tight junctions between the epithelial cells. In contrast, transcellular transport can occur by passive diffusion as well as by active transport, or endocytosis. In general, the hydrophilic molecules diffuse predominantly through the paracellular route, whereas the lipophilic... 

Three processes are involved in transcellular transport across the intestinal epithelial cells simple passive trans-port, passive diffusion together with an efflux pump, and active transport and endocytosis. Simple passive transport is the diffusion of molecules across the membrane by thermodynamic driving forces and does not require direct expenditure of metabolic energy. In contrast, active transport is the movement of molecules across the mem-brane resulting directly from the expenditure of metabolic energy and transport against a concentration gradient. Endocytosis processes include three mechanisms fluid-phase endocytosis (pinocytosis), receptor-mediated endocytosis, and transcytosis (Fig. 6). Endocytosis processes are covered in detail in section Absorption of Polypeptides and Proteins, later. 

Using isolated intact epithelial mucosal preparations, we have shown that, when lithium associated with the extracellular space was taken into account, acute cellular uptake of lithium was negligible (172). This is confirmed by experiments on lithium efflux from everted rings of rat jejunum (173). The recognition that intestinal uptake and transport of lithium may not involve transcellular transport of the metal agrees with proposed transport mechanisms for other alkali metals and magnesium (174). Metal-ion carrier proteins are not essential for rapid absorption of metals to occur their function is to assist when existing equilibrium conditions are unfavorable. 

Enhancement of drug uptake by altered junctional (paracellular) or vesicular (transcellular) transport (Fig. 2) is an active area of research [22,23], The paracellular transport mechanism provides an explanation for the pulmonary absorption of peptides and proteins <40 kDa. 

Early work identified deep lung deposition as an imperative to absorption efficiency, and a number of studies have demonstrated higher bioavailabilites (absorption efficiencies) for peripherally deposited aerosols [51]. However, despite a decade of work, the absorption mechanisms that facilitate transfer from the pulmonary epithelium to the blood are still not well understood. Two mechanisms are believed to operate, transcellular and pericellular. There is some evidence that small invaginations called caveolae may be involved in transcellular transport, whereas pericellular transport is via leaky tight junctions. 

Permeation enhancers improve the absorption of protein and peptides by increasing their paracellular and transcellular transports. An increase in paracellular transport is mediated by modulating the tight junctions of the cells, and an increase in transcellular transport is associated with an increase in the fluidity of the cell membrane. Chapter 2 describes in depth the various paracellular and transcellular transport pathways, which will not be discussed here. 

Calcium is absorbed both actively and passively throughout the small intestine and, to a small extent, in the colon. The active transcellular transport occurs in the duodenum and the passive paracellular process takes place in the jejunum and ileum. The chemical gradient and the sojourn time of the food passing through the intestine determine the movement of calcium that occurs by a passive process. The absorption of calcium in the colon becomes nutritionally significant under conditions of small intestine resection. 

The epithelium (the biological and medical collective term for covering and glandular tissues) is composed of layers of cells that line the outside and inside surfaces of organs. The outermost layer of the skin is composed of stratified squamous epithelial cells, while other epithelial cells line the insides of the respiratory, gastrointestinal, reproductive and urinary tracts, and also comprise the exocrine and endocrine glands. The functions of epithelial cells include secretion, absorption, protection, transcellular transport, sensation detection and selective permeability. The endotheUum-the irmer lining of blood and lymph vessels-is a specialized form of epithelium. 

Figure 4 Transcellular transport in the proximal and distal intestine of the suckling rat. (A) In the proximal intestine, macromolecules may be selectively absorbed in coated pits along luminal membranes (M) and transported via coated vesicles to the basolateral surface (arrows). Alternatively, selection may occur in tubular compartments (T) or from endosomal vesicles (V). (B) In the distal intestine selective absorption may occur in coated pits at the luminal membrane (M) or from the numerous tubules (T) of the elaborate endocytic complex. (From Ref. 18.)...

Based on the majority of observations of particulate uptake in the intestine, transcellular transport, specifically through the epithelium of the Peyer s patch, appears to be the primary pathway of microparticulate absorption (LeFevre and Joel, 1984 Pappo eta/., 1991 Eldridge eta/., 1990 Damge et a/., 1990 Pappo and Erma 1989). Furthermore, most of the transcellular transport involves M cells (Bockman and Cooper, 1973 Joel eta/., 1978, 1970 LeFevre eta/., 1978a), though there have been a few select instances in which other cell types appeared to be involved (Wells et a/., 1988 Landsverk, 1988). 

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