Absorption enhancers bile acids

There are several hypotheses to explain the NSP action on plasma cholesterol, including enhanced bile acid and neutral sterol excretion, the slowing of fat and cholesterol absorption and direct inhibition of hepatic cholesterol synthesis by propionate formed by large bowel fermentation of NSPs. Whole body cholesterol homoeostasis represents a balance between influx and loss. Cholesterol influx can come from dietary intake and de novo synthesis. Losses occur through the sloughing of epithelial cells and through the fecal excretion of nonabsorbed dietary cholesterol and biliary steroids (bile acids and neutral sterols). Bile acids are generally recovered in the ileum, and those that are not absorbed are excreted in the feces. Any increase in bile acid excretion leads to enhanced hepatic uptake of cholesterol and its conversion to bile acids with a consequent depletion of the plasma cholesterol pool. 

Bile acids and salts have been found to enhance the absorption of both calcium and vitamin D hence, to increase calcium absorption both directly and indirectly (3,37). However, the ability of some dietary fibers such as lignin and pectin to absorb conjugated and deconjugated bile salts onto their surfaces to be excreted in the feces (a mechanism credited to the hypocholesterolemic effect of some dietary fibers) may result in an overall decrease in calcium absorption from the gastrointestinal tract (7,33,38-40). 

Other Toxicity Concerns. Additional toxicity concerns include interference with normal metabolism and function of mucosal cells, for example, water absorption by these cells [80]. The unconjugated bile acids are known to block amino acid metabolism [81] and glucose transport [82]. There is a possibility of biotransformation of these enhancers to toxic or carcinogenic substances by hepatic monooxygenases [83]. Absorption of permeation enhancers into the systemic circulation can also cause toxicity, for example, azone [84] and hexamethylene lauramide [85] which are absorbed... 

Bile helps in the digestion and absorption of fats. Its constituent bile acids (BAs) have detergent properties, and some can be carcinogenic. BAs can act as signalling molecules, entering the nuclei and reacting with the nuclear receptors and this could enhance or reduce BA synthesis. In this way, they control their own levels as well as those of their precursor, cholesterol. This controls cholesterol homeostasis and BA and lipid synthesis. 

The addition of absorption enhancers, like bile salts (glycocholate), fatty acids (Unoleic acid), surfactants (lecithins, polyoxyethylene-9-lauryl ether or N-lauryl-P-D-maltopyra-noside) and chelators (EDTA) can significantly increase the absorption of various proteins. However, the application of enhancers is limited by their toxicity. For example polyoxyethyl-ene-9-lauryl ether and sodium glycocholate caused serious oedema, haemorrhage and inflammation of the lung after intratracheal instillation [39]. 

Dimethylhydrazine is well absorbed from the colon of the rat, as shown by an in-vivo perfusion technique (Meshkinpour et al., 1985). The absorption was enhanced significantly by bile acids and by hydroxy-fatty acids fatty acids had no significant effect. 

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. 

A controversial problem is still the selection of suitable enhancing agents to overcome the often limited absorption from the colon. In a survey a number of commonly used enhancers, bile salts, surfactants, fatty acids, glycerides, etc. were also reported as effective in the colon [86],... 

Concomitant intake of food enhances drug absorption, most likely by increasing the degree of gastric dissolution, and decreasing the first-pass effect of spironolactone. The latter effect is possibly due to the secretion of bile acids in response to a meal serving that serves to enhance dissolution of the lipophilic compound [74]. 

Penetration enhancers are substances that can increase the absorption of a co-administered dmg, and include surfactants, bile salts, chelating agents, and fatty acids. Penetration enhancers are widely used in dmg delivery to potentiate absorption across various types of epithelia, including the epithelium of the gastrointestinal tract. However, a major limiting factor in the general acceptance of absorption enhancers for improving oral dmg absorption is the non-specific nature of their effects. 

Emulsification/absorption of dietary lipid in the intestine. Bile acids are stored in the gallbladder and released into the duodenum when cholecys-tokinin is released. In the small intestine, bile acids help to solubilise monoglycerides and fatty acids which are formed as the result of the digestion of dietary triglyceride, thereby enhancing the absorption of lipids and the fat-soluble vitamins A, D, E and K. 

Mixed micelles consist of fatty acids solubilized by surfactants or bile salts. The effects of mixed micelles on drug absorption were reviewed by Muranishi Mixed micelles are effective absorption enhancers for compounds such as heparin, streptomycin, gentamycin, and insulin. The effect of mixed micelles on drug absorption tends to be greater at the distal region of the GI tract. The mechanism for increased absorption is not known. Some publications claim that they are safe to use. Others report a disordering effect on intestinal epithelial cells. 

Yoshioka, S. Caldwell, L. Higuchi, T. Enhanced rectal bioavailability of polypeptides using sodium 5-methoxysalicylate as an absorption promoter. J. Pharm. Sci. 1982, 71, 593-594. Fasano, A. Budillon, G. Guandalini, S. Cuomo, R. Parrilli, G. Cangiotti, A.M. Morroni, M. Rubino, A. Bile-acids reversible effects on small intestinal permeability —an in vitro study in the rabbit. Dig. Dis. Sci. 1990, 55, 801-808. 

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