Bile salts in the intestine

The risk of colon cancer appears to be inversely related to calcium and folate intake. Calciums protective effect may be related to a reduction in mucosal cell proliferation rates or through its binding to bile salts in the intestine, whereas dietary folate helps in maintaining normal bowel mucosa. Additional micronutrient deficiencies have been demonstrated through several studies to increase colorectal cancer risk and include selenium, vitamin C, vitamin D, vitamin E, and 3-carotene however, the benefit of dietary supplementation does not appear to be substantial.11... 

E. Uptake of cholesterol-derived bile salts in the intestine... 

Blockage of the bile duct caused by problems such as cholesterol-containing gallstones or duodenal or pancreatic tumors can lead to an inadequate concentration of bile salts in the intestine. Digestion and absorption of dietary lipids is diminished. Certain diseases that affect the pancreas can lead to a decrease in bicarbonate and digestive enzymes in the intestinal lumen. (Bicarbonate is required to raise the intestinal pH so that bile salts and digestive enzymes can function.) If dietary fats are not adequately digested, steatorrhea may result. Malabsorption of fats can lead to caloric deficiencies and lack of fat-soluble vitamins and essential fatty acids. 

Cholestyramine is another treatment option for cholestasis of pregnancy. It is an oral medication that binds bile salts in the intestine and promotes their excretion in the feces. As this drug is not absorbed, it most likely has little effect on the fetus. Effects on the fetus are stiU under evaluation. However, cholestyramine can interfere with the absorption of fat soluble vitamins, such as vitamins A, D, E, and K. In rare cases, drug-induced vitamin K deficiency is believed to contribute to hemorrhaging during childbirth. 

Like cholesterol, fat-soluble vitamins are strongly dependent on the presence of bile salts in the intestinal lumen for their absorption. Using thoracic duct lymph samples to estimate their absorption, Forsgren [98] showed marked depression of absorption of radiolabeled vitamins A, D, E and K in patients with total biliary obstruction. Intraluminal bile salt deficiency probably also contributes to impaired vitamin D absorption in primary biliary cirrhosis [99]. When exocrine pancreatic insufficiency is also present, absorption of vitamin K is even more markedly impaired [98]. More polar subspecies of the fat-soluble vitamins such as vitamin K3 [100] and 25-hydroxyvitamin D, [101] depend much less on bile salts for their absorption. 

In animal studies, absorption of vitamin D [102] and E [103] has been shown to depend on the presence of bile salts in the intestine. In rats, a polar lipid, oleic acid, is absorbed almost as well from an emulsion as from a micellar solution while a-tocopherol uptake from an emulsion was much less than from a micellar solution... 

How bile salts promote fat-soluble absorption of vitamins is not fully understood. It is likely that several mechanisms are involved. For example, there is evidence that handling of certain of the fat-soluble vitamins in the enterocyte is influenced by bile salts. In the intestinal lumen, it is likely that a suitable solubilizing phase, liposomal or micellar, involving bile salts, monoglycerides and fatty acids creates a sufficiently high concentration of such lipids of low polarity close to the brush border membrane of the enterocyte. 

These drugs are non-absorbable, charged polymers which bind ionically charged bile salts in the intestinal lumen. 

Because Ann Jeina continued to experience intermittent chest pain, in spite of good control of her hypertension and a 20-lb weight loss, her physician decided that a 2-drug regimen to lower her blood LDL cholesterol level must be added to the dietary measures aheady in place. Consequently, treatment with cholestyramine, a resin that binds some of the bile salts in the intestinal lumen, and the HMG-CoA reductase inhibitor pravastatin was initiated. 

Ann Jeina was treated with cholestyramine, a resin that binds some of the bile salts in the intestine, causing these resin-bound salts to be carried into the feces rather than recycled to the liver. The liver must now synthesize more bile salts, which lowers the intrahepatic free cholesterol pool. As a result, hepatic LDL receptor synthesis is induced, and more circulating LDL is taken up by the liver. 

One idea for treating hypercholesterolemia is to decrease the reabsorption of bile salts from the intestinal contents by ingesting anion-exchange resin that retains the bile salts in the intestinal lumen (Sec. 12.2). The liver, however, responds by synthesizing more cholesterol so the treatment is not as effective as might have been anticipated. 

Microspheres have also shown potential as carriers for oral vaccine delivery. The protective polymer coating of microspheres is believed to partially shield the antigens from destructive pH of the stomach, and the high levels of proteases and bile salts in the intestine. Furthermore, microspheres smaller than 10 pm in diameter are thought to be at least partially taken up from the intestine into Peyer s patches where they can induce both mucosal and systemic immune responses. " ... 

A nonabsorbable strongly basic anion exchange resin which binds bile salts in the intestinal lumen, thereby removing them from the enterohepatic circulation for excretion in the feces, will relieve pruritus in patients who do not have complete biliary obstruction. When serum bile salt concentrations are measured serially at frequent intervals during cholestyramine feeding, it can be shown that concentrations reach near normal levels before pruritus stops, and when cholestyramine is withheld, high serum concentrations are reached before pruritus starts. This lag period, which may be a day or more, may represent the period of time required for concentrations of bile salts sufficient to induce pruritus to accumulate in or leave the skin (57). 

Increased levels of bile acids in the serum are found in hepatitis and obstructive jaundice. In cholestatic liver disease, there can be a deficiency of bile salts in the intestine and this leads to fat malabsorption. Disturbances in bile acid composition may be one of the factors involved in gallstone formation because it may lead to conditions favouring cholesterol precipitation. 

Blood-cholesterol-lowering agents—It is suspected that the types of these drugs which bind with cholesterol and bile salts in the intestine may similarly tie up calcium and other minerals so that their absorption is reduced. 

This fundamental role of bile salts in the intestinal absorption of sterols is a reflection of the potential requirements for this cholesterol metabolites in various steps of intraluminal and epithelial cell mechanisms of cholesterol absorption (Figure 1), These include solubilization of cholesterol in the intestinal lumen by mixed micelles, containing biliary bile salts and phospholipids, and the products of triglyceride digestion modification of the intestinal surface barriers to cholesterol transfer, including the un-stirred water layer" and the mucin "coat" and the cellular esterification of cholesterol prior to incorporation of the resulting esters into the lipoprotein core lipids. 

The most common manner to study apparent solubility will be to conduct the shake flask method as described above, but instead of waiting for 24 h the sample will be assayed at earlier time points (1, 2, 4 h...) to generate a plot of apparent solubility versus time. This profile should be measured at multiple pH values to see how the apparent solubility will be affected by different pH values. Finally, the use of surfactants will typically be studied. This has some biorelevance, since there are a number of bile salts in the intestine that will have a surfactant effect. Also this will provide valuable technical information for solubilizing the API for sample preparation, dissolution testing, as well as utilizing surfactants in the drug product. 

Hypersecretion of acid leads to precipitation of bile salts in the intestine and malabsorption syndromes. Neomycin and kanamycin precipitate bile salts and among other adverse effects also lead to malabsorption [220]. 

A review by Heaton and Morris [221] recalls the development of ideas about bile salts and "bitter humour. The enterohepatic circulation of the bile salts was an early discovery the site of absorption of the bile salts in the intestine was a later topic of study. Absorption by the jejunum of sodium taurocholate is negligible both below and above the CMC and it was absorbed mostly in the ileum [222]. It has been established that bile salts are absorbed by an active transport process, absorption being related to the number of hydroxyl groups on the molecule. 

A logical extension of this type of study, because of the natural presence of bile salts in the intestine and the presence of synthetic surfactants in formulations, is the consideration of bile salt-surfactant mixtures. One such study [118] has considered the effect of sodium glycocholate and its mixtures with NaLS and polysorbate 80 on the absorption and metabolism of a thiamine disulphide derivative, in rats (see Scheme 7.1). It had previously been shown that surfactants altered the reaction rates of the thiol-disulphide exchange reaction that these compounds undergo [119] and that o-benzoyl thiamine disulphide interacts with the lauryl sulphate anion to form a 1 2 complex this complex is broken up by sodium glycocholate to form new mixed micelles of thiamine derivatives and the surfactants. NaLS decreases /c and /c promoting the conversion of V to VII. The reduction in absorption and the decreased enzymatic deacylation are both explained by complex formation, although inactivation of intestinal esterase by... 

In obstructive jaundice, lack of the bile salts in the intestine gives rise to digestive disturbances due to the inability to absorb the hydrolysed fat. 

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