Bile acid reabsorption

Bile acid sequestrants l Bile acids reabsorption t LDLR activity... 

Partial ileal bypass has been used in severe heterozygous and homozygous familial hypercholesterolemia however, it is ineffective in the latter case. Ileal bypass removes the site of bile acid reabsorption, depleting the bile acid pool and increasing the catabolism of cholesterol. A randomized trial of diet versus surgery, called Program On the Surgical Control of the Hyperlipidemias (POSCH), reported... 

The first such inhibitors consisted of the coupling of two bile acid molecules by means of a spacer to allow simultaneous interaction with more than one transporter site, resulting in an efficient inhibition of bile acid reabsorption without or with only low absorption of the inhibitor itself (110) (Fig. 8.13). Recently, it was shown that a benzothiazepine derivative, 2164U90, was able to selectively inhibit active ileal bile acid absorption in rats, mice, mon-... 

Of the hyperlipidemic drugs, clofibrate appears to decrease fecal elimination of bile acids (278-280). However, this decrease is less than the increase of the neutral steroid output, so the net elimination of cholesterol is increased (280). Thyroid hormones may occasionally, especially if associated with diarrhea, cause a marked increase in bile acid elimination (see Section VIIB), while nicotinic acid only occasionally augments fecal bile salt output (221, 281). Of the more recently developed absorbable hypolipidemic drugs, DH-581 appears to stimulate bile acid excretion at least transiently, probably by inhibiting intestinal bile acid reabsorption (282). 

Cholesterol is supplied by absorption from diet (0.3-0.5 gfday in human) and biosynthesis (1.0-1.2 g/day) and is excreted mainly as bile acids into feces (0.8-1.3 g/day) (8). To reduce body cholesterol, three major strategies can be considered (a) inhibition of cholesterol absoipticm by a compound such as sitosterol, (b) inhibition of bile acid reabsorption by a compound such as cholestyramine, and (c) inhibition of cholesterol biosynthesis. Since more chan 70% of the total input of body cholesterol in humans is derived from de novo synthesis, it is expected that plasma cholesterol levels can be reduced by inhibition of cholesterol biosynthesis. 

In 1953, SiPERSTEiN et al. [437] suggested that inhibition of bile acid reabsorption from the intestinal tract might be an effective means for controlling hypercholesterolemia. This was, indeed, shown to be possible with absorbants such as ferric chloride [437], dietary saponins [438] and pectins [439]. 

Bile acid reabsorption inhibitors On the way to novel hypolipidemic drugs... 

Anion exchange resins are basic polymers with a high affinity for anions. Because different anions compete for binding to them, they can be used to sequester anions. Clinically used anion exchange resins such as cholestyramine are used to sequester bile acids in the intestine, thereby preventing their reabsorption. As a consequence, the absorption of exogenous cholesterol is decreased. The accompanying increase in low density lipoprotein (LDL)-receptors leads to the removal of LDL from the blood and, thereby, to a reduction of LDL cholesterol. This effect underlies the use of cholestyramine in the treatment of hyperlipidaemia. 

The answer is a. (Katzung, p 590.) Bile acids are absorbed primarily in the ileum of the small intestine. Cholestyramine binds bile acids, preventing their reabsorption in the jejunum and ileum. Up to 10-fold greater excretion of bile acids occurs with the use of resins. The increased clearance leads to increased cholesterol turnover of bile acids. Low-density lipoprotein receptor upregulation results in increased uptake of LDL. This does not occur in homozygous familial hypercholesterolemia because of lack of functioning receptors. 

The mechanisms by which various forms of dietary fiber influence calcium bioavailability apparently also differ. In some cases, apparent dietary fiber effects on calcium bioavailability may be secondary to effects on bile acid and salt secretion and reabsorption or to other dietary components. 

Its target genes regulate the secretion of bile acids and phospholipids into bile (bile salt efflux pump, MDR2 and 3), the intestinal reabsorption of bile add (ileal bile... 

Drugs Drugs that lower the blood levels of cholesterol are frequently used as part of the treatment these include (i) Oral bile acid binding exchange resins. Resins such as cholestyramine are effective because, when taken by mouth, they prevent the reabsorption of bile acids in the lower small intestine, so that they are excreted in the faeces. Since bile acids are formed in the liver from cholesterol, synthesis of more acids requires more cholesterol uptake by the liver from the blood, which occurs via LDL-cholesterol, so that the concentration of the latter is decreased. 

In the bile cholesterol is kept soluble by fats, phospholipids like lecithin and by bile acids. The important bile acids in human bile are cholic acid, chen-odeoxycholic acid or chenodiol and ursodeoxycholic acid or ursodiol. Bile acids increase bile production. Dehydrocholic acid, a semisynthetic cholate is especially active in this respect. It stimulates the production of bile of low specific gravity and is therefore called a hydrocholeretic drug. Chenodiol and ursodiol but not cholic acid decrease the cholesterol content of bile by reducing cholesterol production and cholesterol secretion. Ursodiol also decreases cholesterol reabsorption. By these actions chenodiol and ursodiol are able to decrease the formation of cholesterolic gallstones and they can promote their dissolution. 

The liver secretes about 1 L of bile daily. Bile flow and composition depend on the secretory activity of the hepatic cells that line the biliary canaliculi. As the bile flows through the biliary system of ducts, its composition can be modified in the ductules and ducts by the processes of reabsorption and secretion, especially of electrolytes and water. For example, osmotically active compounds, including bile acids, transported into the bile promote the passive movement of fluid into the duct lumen. In the gallbladder, composition of the bile is modified further through reabsorptive processes. 

Mechanism of Action A lipid-bile acid sequestrant and nonsystemic polymer that binds with bile acids in the intestines, preventing their reabsorption and removing them from the body Therapeutic Effect Decreases LDL cholesterol. Pharmacokinetics Not absorbed. Primarily eliminated in feces. 

The bile acid-binding agents are large polymeric cationic exchange resins that are insoluble in water. They bind bile acids in the intestinal lumen and prevent their reabsorption. The resin itself is not absorbed. 

Colestipol Binds bile acids in gut prevents reabsorption increases cholesterol catabolism up-regulates LDL receptors Decreases LDL Elevated LDL, digitalis toxicity, pruritus Oral taken with meals not absorbed Toxicity Constipation, bloating interferes with absorption of some drugs and vitamins... 

Among the different roles previously described, the liver exerts an excretory function, being involved in the formation of bile, which drains into the small intestine. Bile salts in the bile play an important role as emulsifying agents for the reabsorption of lipids and fatty acids from the intestine. Hepatic and obstructive biliary diseases lead to abnormal metabolism of bile acids (BAs). 

Bile salts secreted into the intestine are efficiently reabsorbed (greater than 95 percent) and reused. The mixture of primary and secondary bile acids and bile salts is absorbed primarily in the ileum. They are actively transported from the intestinal mucosal cells into the portal blood, and are efficiently removed by the liver parenchymal cells. [Note Bile acids are hydrophobic and require a carrier in the portal blood. Albumin carries them in a noncovalent complex, just as it transports fatty acids in blood (see p. 179).] The liver converts both primary and secondary bile acids into bile salts by conjugation with glycine or taurine, and secretes them into the bile. The continuous process of secretion of bile salts into the bile, their passage through the duodenum where some are converted to bile acids, and their subsequent return to the liver as a mixture of bile acids and salts is termed the enterohepatic circulation (see Figure 18.11). Between 15 and 30 g of bile salts are secreted from the liver into the duodenum each day, yet only about 0.5 g is lost daily in the feces. Approximately 0.5 g per day is synthesized from cholesterol in the liver to replace the lost bile acids. Bile acid sequestrants, such as cholestyramine,2 bind bile acids in the gut, prevent their reabsorption, and so promote their excretion. They are used in the treatment of hypercholesterolemia because the removal of bile acids relieves the inhibition on bile acid synthesis in the liver, thereby diverting additional cholesterol into that pathway. [Note Dietary fiber also binds bile acids and increases their excretion.]... 

Cholestyramine or colestipol form an insoluble complex with the bile acids and salts, preventing their reabsorption from the intestine. 

---