Taurocholic acid absorption

OATP2B1 (old name OATP-B) is expressed at brush-border membranes of intestinal epithelial cells [32], OATP2B1 exhibited pH-sensitive transport activities for various organic anions such as estrone-3-sulfate, dehydroepiandros-terone sulfate, taurocholic acid, pravastatin, and fexofenadine [33], However, further studies are needed to determine the specific physiological and pharmacokinetic contribution of OATP2B1 for intestinal absorption of these compounds. 

Does Citrus Pectin Bind Bile Salts A possible mechanism by which dietary pectin may cause lowering of cholesterol levels in rats has been reported (1 9). In these in vitro studies, pectin was found to inhibit the transport of taurocholic acid from everted sacs of rat intestine. The absorption of labelled cholesterol was depressed by the addition of 5% pectin to the diet as evidenced by increased excretion of labelled cholesterol and diminished cholesterol deposition in the liver. It was concluded from these studies that pectin lowers cholesterol levels in cholesterol-fed rats primarily by binding bile salts and, consequently, by impairing cholesterol absorption. Results similar to those obtained with dietary pectin and described have also been reported for other non-nutritive substances such as guar gum, psyllium seed colloid and seruglucan (20). 

Consequently, absorption enhancers were used in dry powder and liquid formulations to enhance the pulmonary absorption of SCT. Without absorption enhancers, SCT absorption from dry powder or solution was similar to that observed after intratracheal administration. However, the absorption was more improved from dry powder than from solution when absorption enhancers (oleic acid, lecithin, citric acid, taurocholic acid, dimethyl-[5-cyclodextrin, octyl-P-D-glu-coside) were co-administered intratracheally. Such improved absorption could be due to the fact that enhancers added to the dry powder dissolved at high concentration because only a trace volume of fluid lining the alveolar epithelium was available for their dissolution. However, the potential implications of such a mechanism on lung toxicity, especially in lung edema, is yet to be investigated in detail [68]. 

Finally, the existence in CF of a primary ileal mucosal defect for BA absorption has been recently investigated. The ileal mucosal uptake of taurocholate in vitro was found to be reduced in CF patients and comparable to those for passive jejunal taurocholic acid uptake in controls. An incapacity of the ileus to actively transport BA in CF has therefore been suggested, similarly to other small bowel mucosal dysfunctions previously described in this disease. 

In culture, the human colon carcinoma cell hne Caco-2 spontaneously differentiates at confluency into polarized cells with enterocyte-like characteristics. The principle of this approach consists of following the passage of the compound of interest from the apical or lumen-like sides to the basolateral or lymph-hke sides of Caco-2 cells, thus following the absorption of the compound per se. One obhgate step for fat-soluble nutrients such as carotenoids to cross the intestinal barrier is their incorporation into CMs assembled in the enterocytes. Under normal cell culture conditions, Caco-2 cells are unable to form CMs. When supplemented with taurocholate and oleic acid, Caco-2 cells were reported to assemble and secrete CMs. ... 

In contrast to previous in vivo models, this in vitro model provides the possibility of dissociating experimentally two important processes of intestinal absorption cellular uptake and secretion. Under conditions mimicking the postprandial state (taurocholate/oleic acid supplementation), differentiated Caco-2 cells were able to (1) take up carotenoids at the apical sides and incorporate them into CMs and (2) secrete them at the basolateral sides associated with CM fractions. Using this approach, the extent of absorption of P-carotene through Caco-2 cell monolayers after 16 hr of incubation was 11.2%, a value falling within the in vivo range (9 to 22%). ° - Of the total amount of P-carotene secreted, 78% was associated with the two CM fractions and 10% with the VLDL fraction. ... 

When diabetic rabbits (24) were treated with 50 IU of bovine insulin imbibed at 50 mg/g poly (acrylic acid) (Figure 14) no reduction in serum glucose over that achieved by the dry blend control could be detected. Pretreatment of the animals with oral doses of either a penetration enhancer, sodium taurocholate, or a protease inhibitor, aproteinin, failed to improve the insulin activity. One possible explanation for this unexpected lack of activity might be that the diseased animals exhibit impaired ileal absorption of fluids (25). 

Intestinal absorption studies of Mn-MP were undertaken in an effort to assess the viability of the metalloporphyrin as an oral hepatobiliary agent [101, 102]. Mixed micelles of Mn-MP complexed with monoolein and taurocholate were administered to rats, resulting in liver image enhancement 68% above baseline levels six hours after administration [101]. In pigs, the mixed micelle preparation showed variable enhancement over 24 hours. Observation that Mn-MP interacts with oleic acid vesicles [103] led to investigations of the effect of oleic acid on the absorption rate of Mn-MP from the small bowel into the circulatory system [102,104]. The increase in absorption of the complex was mediated by a decrease in the relaxivity of the metalloporphyrin resulting from the interaction with the lipid vesicles. 

An example of the correlations obtained in small intestine in the absence and in the presence of tetradecyltrimethylamonium bromide (TTAB) at 0.0125% (CMC) is represented in Fig. 4.4 [26]. As can be seen, the effect of each surfactant concentration is quite significant. But, a natural surfactant such as sodium taurocholate did not produce any significant change in the absorption rate constants of a series of phenyl-alkyl carboxylic acids at its CMC and it exerted an almost negligible solubilization effect at a supramicellar concentration [23]. 

Fig. 4.5 Absorption-partition correlations obtained in rat stomach for a series of acid xenobiotics in absence of any additive (ka) and in presence of sodium taurocholate (NaT) and Tween 80 at a concentration below its CMC. (Adapted from Garrigues et al. [8]).

The possible reasons for the different behavior of natural surfactants could include the following. Natural surfactants lead to surface tension values higher than those corresponding to the same concentration of a synthetic surfactant. The ability to nullify the aqueous layer resistance could be related with the surface tension values. However, the micelles of bile salts are smaller and more rigid than the micelles of synthetic surfactants. The solubilization potential of bile salts is increased in the presence of lecithins and fatty acids. For instance, the absorption rate constants obtained in the presence of sodium taurocholate and glycocholate mixed-micelles with lecithin for a series of acids were significantly lower than those obtained in the presence of simple micelles of the same bile salts [29, 30]. 

The mechanism of the inhibition of the HMG-CoA reductase by bile adds shown in Fig. 14 is a matter of controversy. Weis and Dietschy did not observe any influence of taurocholate on cholesterol synthesis in bile fistula rats fed a cholesterol-free diet, and concluded that the inhibitory effect of bile acids on cholesterol synthesis may be related to the increased absorption of cholesterol by the presence of bile acids in the intestine [247]. However, Hamprecht et al. were able to demonstrate a reduction of HMG-CoA reductase activity in lymph fistula rats infused with cholate [248]. Results by Shefer et al. also indicate that bile acids inhibit HMG-CoA reductase directly [212]. It seems likely that the inhibitory effect of the bile acids on HMG-CoA reductase may involve both direct and indirect effects. It was recently established that the stimulation of HMG-CoA reductase activity in response to treatment with cholestyramine is associated with an increase of the specific mRNA [258]. 

A direct effect of luminal lipids on the absorption of bile salts has been found by Sklan and Budowski [75], Taurocholate uptake was determined in situ in segments of rat small intestine, and jejunal absorption increased when taurocholate was injected together with oleic acid, monoolein, PC or lyso-PC. For each lipid a certain molar ratio of lipid to bile salt was found that resulted in an optimal uptake of taurocholate. In contrast, the active uptake of bile salts by isolated intestinal villi preparations of hamster distal ileum has been found to be inhibited by dietary lipids [76]. 

Bile salts are detergent-like substances secreted from the gallbladder that aid in the digestion and absorption of lipids. A bile salt is made up of a bile acid and an associated cation, usually an amino acid. Examples include glycocholate and taurocholate. 

Samples of lignin, wood, or cellulose were suspended in phosphate buffer (pH 7.0, y = 0.5) containing varying concentrations of sodium cholate, sodium deoxycholate or sodium taurocholate. The concentration remaining in the supernatant after equilibration for 20-24 h was determined by measuring the absorption spectra of polyenylic carbocations formed from bile acids in 72% sulfuric acid ( ). ... 

Studies with radioactive glycocholate or taurocholate demonstrated a virtual absence of the enterohepatic circulation of bile acids in patients with jejunotransversocolostomy (77). The small amount of absorbed bile acids contained some deconjugated cholate and deoxycholate (which had been reconjugated in the liver), indicating a rapid bacterial action during an apparently fast intestinal passage. Under these conditions, steatorrhea is apparently not solely due to bile salt deficiency induced impairment of micelle formation, but reduced absorptive area may play an important contributory role. No direct measurement of bile acid synthesis by fecal determination has been performed in this condition. 

In contrast, in ileal absorptive disorders, Garbutt et al. (38) observed an increase in G T ratios of both cholate and deoxycholate, which was attributed to a decrease in enterohepatic recirculation of taurocholate and deoxycholate. It is also interesting to note that a selective conjugation of cholic acid with L-ornithine could be induced in the rat and guinea pig liver by the injection of a toxic capsular polysaccharide of Klebsiella pneumoniae (39). Partial hepatectomy has also been shown to result in a shutdown in the hepatic synthesis of glycine conjugates of bile acids (40). 

Agents capable of promoting absorption and/or permeation were discussed in a recent review . The intestinal absorption of sulfamethoxypyridazine, diphenhydramine, salicylic acid, p-hydroxybenzoic acid and heparin was facilitated in the presence of surfactants, as was the intramuscular absorption of enduracidin . The effect of sodium taurodeoxycholate on drug transport across biological barriers was studied " . Mixed micellar solutions of a fatty acid, a monoglyceride and sodium taurocholate had a greater effect on the absorption of... 

Several lines of evidence suggest that, in addition to a requirement for an intact enterohepatic circulation of,bile, cholesterol absorption is dependent on the chemical nature of the luminal bile acid. In acute studies on the absorption of cholesterol in thoracic duct lymph of rats, a quantitative relationship between administered cholesterol, fatty acids and sodium taurocholate was... 

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