Epithelia absorptive

Diuretics promote the urinary excretion of sodium and water by inhibiting the absorption of filtered fluid across the renal tubular epithelium. The ensuing reduction in Na reabsorption reduces the Na content of the body, the critical determinant of extracellular and plasma fluid volumes. Thus, the use of diuretics is primarily indicated in the treatment of edematous diseases and of arterial hypertension. 

Delivery of peptides and proteins via the gastrointestinal tract has not been successful because of poor penetration through the intestinal epithelium and high levels of proteolytic activity in the gastrointestinal tract. Liposomal encapsulation of proteins and peptides will not improve the efficiency and capacity of this absorption pathway considerably (e.g., Ryman et al., 1982 Machy and Leserman, 1987 Weiner and Chia-Ming Chiang, 1988). These difficulties in delivery via the oral route caused the parenteral route to remain the preferred route for the administration of therapeutic peptides... 

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR), a chloride (CF) channel characterised by chloride permeability and secretion, and also by the regulation of other epithelial ion channels (Eidelman et al, 2001). Mutations in the CFTR gene lead to an impaired or absent Cl conductance in the epithelial apical membrane, which leads to defective Cl secretion and absorption across the epithelium. Genistein (Illek et al, 1995 Weinreich et al, 1997) and other flavonoids (Illek and Fisher, 1998) have been shown, in different animal and tissue models, to activate wild-type CFTR and CFTR mutants by (Eidelman et al, 2001 Roomans, 2001 Suaud et al, 2002) ... 

Curcumin possesses strong antioxidant capacities, which may explain its effects against degenerative diseases in which oxidative stress plays a major role. As previously described for flavonoids, it is unlikely that curcumin acts as a direct antioxidant outside the digestive tract since its concentration in peripheral blood and organs is very low (near or below 1 pM, even after acute or long-term supplementation). Indeed, it has been shown that the intestinal epithelium limits its entry into the body, as reflected by absorption studies in various models (portal blood perfusion, everted bags). ... 

The passage of fluids into and out of the colon is regulated by epithelial cells. In IBS, the colonic lining (epithelium) appears to work properly. However, increased movement of the contents in the colon can overwhelm its absorptive capacity. 

Mucin, a viscous mucopolysaccharide that lines and protects the intestinal epithelium, has been thought to bind certain drugs nonspecifically (e.g., quarternary ammonium compounds) and thereby prevent or reduce absorption. This behavior may partially account for the erratic and incomplete absorption of such charged... 

JS Trier. Morphology of the epithelium of the small intestine. In CF Code, ed. Handbook of Physiology. Vol. Ill, Intestinal Absorption. Washington, DC American Physiological Society,1968, p. 1133. 

M Bendayan, E Ziv, R Ben-Sasson, H Bar-On, M Kidron. Morpho-cytochemical and biochemical evidence for insulin absorption by the rat ileal epithelium. Diabeto-logia 33 197-204, 1990. 

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-... 

Although the ocular absorption of peptide as well as nonpeptide drugs is poor [96,196-198], the ocular route is by far the least studied for the usefulness of penetration enhancers. This is in part due to the perceived sensitivity of ocular tissues to irritation and the fear of corneal and conjunctival damage caused by the enhancers. Whereas the rat nasal epithelium may tolerate up to 5% sodium glycocholate [199], ocular administration of sodium glycocholate at a concentration of 2% and beyond induces reddening of the eye and tear production in rabbits (Kompella and Lee, unpublished observation). 

Morimoto et al. [33] demonstrated that the ocular absorption of hydrophilic compounds over a wide range of molecular weights could be increased by 2 and 10 mM sodium taurocholate and sodium taurodeoxycholate in a dose-dependent manner. The compounds were glutathione (307 Da), 6-carboxyfluorescein (376 Da), FTTC-dextran (4 kDa), and insulin (5.7 kDa). Of the two bile salts, sodium taurodeoxycholate was more effective. At 10 mM, this bile salt increased the permeability of 6-carboxyfluorescein from 0.02% to 11%, glutathione from 0.08% to 6%, FITC-dextran from 0% to 0.07%, and insulin from 0.06% to 3.8%. Sodium taurocholate, on the other hand, increased the permeability to 0.13%, 0.38%, 0.0011%, and 0.14%, respectively. Taurodeoxycholate was more effective than taurocholate in the nasal epithelium as well [202], This difference in activities can possibly be attributed to their micelle-forming capability, which is higher for taurodeoxycholate, a dihydroxy bile salt [190],... 

Numerous observations of non-linear relationships between PbB concentration and lead intake in humans provide further support for the existence of a saturable absorption mechanism or some other capacity limited process in the distribution of lead in humans (Pocock et al. 1983 Sherlock et al. 1984, 1986). However, in immature swine that received oral doses of lead in soil, lead dose-blood lead relationships were non-linear whereas, dose-tissue lead relationships for bone, kidney and liver were linear. The same pattern (nonlinearity for PbB and linearity for tissues) was observed in swine administered lead acetate intravenously (Casteel et al. 1997). These results suggest that the non-linearity in the lead dose-PbB relationship may derive from an effect of lead dose on some aspect of the biokinetics of lead other than absorption. Evidence from mechanistic studies for capacity-limited processes at the level of the intestinal epithelium is compelling, which would suggest that the intake-uptake relationship for lead is likely to be non-linear these studies are discussed in greater detail in Section 2.4.1. 

Chong, S., S. A. Dando, and R. A. Morrison. Evaluation of Biocoat intestinal epithelium differentiation environment (3-day cultured Caco-2 cells) as an absorption screening model with improved productivity, Pharm. Res. 1997, 34, 1835-1837... 

Muranishi, S., Yamamoto, A., Mechanisms of absorption enhancement through gastrointestinal epithelium, in Drug Absorption Enhancement, de Boer, A. G. (ed.), Harwood Academic Publishers, 1994, 67-100. 

More recently, P-gp has been shown to be expressed in normal human tissues. In the gut, the expression is highly localized to the apical surfaces of the gut wall epithelium [30], where it is well placed to intercept its substrates and deposit them back into the lumen of the gut in a counter-absorptive manner. 

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