Transport system bile salt

Bile is produced continuously by the liver bile salts are secreted by the hepatocytes and the water, sodium bicarbonate, and other inorganic salts are added by the cells of the bile ducts within the liver. The bile is then transported by way of the common bile duct to the duodenum. Bile facilitates fat digestion and absorption throughout the length of the small intestine. In the terminal region of the ileum, the final segment of the small intestine, the bile salts are actively reabsorbed into the blood, returned to the liver by way of the hepatic portal system, and resecreted into the bile. This recycling of the bile salts from the small intestine back to the liver is referred to as enterohepatic circulation. 

Wieland, T., et al. Identity of hepatic membrane transport systems for bile salts, phalloidin, and antamanide by photoaffinity labeling. Proc. Natl. Acad. Sci. U. S. A. 1984, 81, 5232-5236. 

As mentioned above, the rectal route is very attractive for systemic delivery of peptide and protein drugs, but rectal administration of peptides often results in very low bioavailability due to not only poor membrane penetration characteristics (transport barrier) but also due to hydrolysis of peptides by digestive enzymes of the GI tract (enzymatic barrier). Of these two barriers, the latter is of greater importance for certain unstable small peptides, as these peptides, unless they have been degraded by various proteases, can be transported across the intestinal membrane. Therefore, the use of protease inhibitors is one of the most promising approaches to overcome the delivery problems of these peptides and proteins. Many compounds have been used as protease inhibitors for improving the stability of various peptides and proteins. These include aprotinin, trypsin inhibitors, bacitracin, puromycin, bestatin, and bile salts such as NaCC and are frequently used with absorption enhancers for improvement in rectal absorption. 

BSEP also known as sister-P-glycoprotein (SPGP) was originally cloned from pig liver (185). BSEP is localized on the canalicular membrane of hepa-tocytes and is responsible for the secretion of bile salts across the canalicular membrane into bile. BSEP appears to be the predominant bile salt efflux system for hepatocytes, and is a critical component in the enterohepatic circulation of bile acids. A number of mutations in the transporter were found to the basis for progressive familial intrahepatic cholestasis type 2 (PFIC2) (186-188). Mutations found in PFIC2 patients include frameshifts, missense mutations, and premature termination codons. Most PFIC2 patients lack immunohistochemically detectable BSEP in their liver. Recently, seven... 

In summary, triacylglycerols from the diet are digested by lipase and associate with bile salts into mixed micelles. The free fatty acids are absorbed by the cells of the small intestine, from which they are transported via the lymph system to the liver. From the liver, they are released as apolipoproteins in the circulation, carrying fatty acids and cholesterol to the cells throughout the body. 

ABCA1 mediates the first step in the energy-dependent efflux of cholesterol from the cell to form HDL for reverse cholesterol transport (Fig. 15-2). While all tissues in the body can synthesize cholesterol, only the liver and steroidogenic tissues can metabolize it. Surplus cholesterol in cells of the peripheral tissues is transported to the liver for either redistribution to other cells or for excretion either as free cholesterol or as a bile salt after conversion in the liver. Therefore, this reverse cholesterol transport system plays a pivotal role in cholesterol homeostasis with HDL as one of the key players. 

Cholestatic Mechanisms Sinusoidal transporters and canalicular transporters are involved in the movement of bile salts from the sinusoids into the canahculi. Within the hepatocyte, transcytosis is mediated by cytoskeletal transport mechanisms. Bile is moved within the canaliculi through actions of the hepatocyte cytoskeleton causing contraction of the canalicular lumina (Treinen-Moslen, 2001). Xenobiotics acting on any of the above systems may influence bile transport and secretion. 

This volume of secretion is supplemented in the ductules by ca. 150 ml ductular bile, resulting in a daily production of ca. 600 ml. Bile formation is lower at night than during the day. The most important constituents of the so-called liver bile are the bile acids, phospholipids, proteins, cholesterol and bilirubin. The term bile lipids includes cholesterol, bile salts and phospholipids. The manner in which cholesterol is excreted into the gall bladder is not yet known, nor have any cholesterol-specific transport systems been detected. Cholesterol is primarily broken down into bile acids, (see above) (s. tab. 3.5)... 

Many studies have been completed in order to assess the effect of bile salts on the bioavailability of poorly soluble drugs. Bile salts for example, have been shown to enhance the absorption of sulphaguanidine and urogastrone. Bile salts may also play a role in enhancing the transport of a compound from the lumen of the intestine to the systemic circulation. Such absorption involves overcoming the resistance of the aqueous boundary layer and the membrane epithelium to the passage of the drug. 

Preformed vitamin A, most often in the form of retinyi ester, or carotenoids are subject to emulsification and mised micelle formation by the action of bile salts before being transported into the intestinal cell. Here the retinyi esters are moved across the mucosal membrane and hydrolyzed to retinol within the cell to then be reesterified by cellular retinol-binding protein II and packaged into chylomicra, which then enter the mesenteric lymphatic system and pass mto the systemic circulation. A small amount of the ingested retinoid is also converted into retinoic acid in the intestinal cell. The efficiency of absorption of preformed vitamin A is high at between 70% and 90%. ... 

Most dietary riboflavin is taken in as a complex of food protein with the coenzymes FMN and FAD. These coenzymes are released from noncovalent attachment to proteins as a consequence of gastric acidification. Nonspecific action of pyrophosphatase and phosphatase on the coenzyme occurs in the upper gut. The vitamin is primarily absorbed in the proximal small intestine by a saturable transport system that is rapid and proportional to intake before leveling off at doses near 27 mg riboflavin per day. Bile salts appear to facilitate the uptake, and a modest amount of the vitamin circulates via the enterohepatic system. Active transport at lower levels of intake was thought to be sodium ion-dependent and involve phosphorylation, though later work has suggested that uptake is independent of sodium... 

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