Circulation, enterohepatic

The process of bile acid formation in the liver, movement to the gallbladder, and then movement to the duodenum is a pathway that can concentrate toxicants in hepatocytes. From the gallbladder where they are stored, bile acids are released into the gut to aid in the digestion of lipophobic substances. Most of the released bile acids are reabsorbed in the intestines and are returned to the liver by the hepatic portal circulation. 

Results of studies over a period of about 20 years confirm that cytoplasm is the major suhcellular location of bile acids in rat liver [9-11] and that cholic acid is the major bile acid. Kurtz et al. [10] reported 64% of hepatic bile acids in cytosol, 33% in microsomes, and 3% in mitochondria of male rats, and 69%, 26% and 6%, respectively in these fractions of female rat liver. Table 1 shows the relative proportions of 7 non-sulfated bile acids in these fractions of liver from male and female rats [10]. 

Percentage of non-sulfated bile acids in rat liver subcellular fractions  

lithocholate DC, deoxycholate CDC, chenodeoxycholate HDC, hyodeoxycholate yS-MC, 8-muricholate a-MC, -muricholate C, cholate Others, unidentified by difference to equal 100% X = mean value values considered significant if p was less than 0.05 N.S., not significant. 

Sex differences were marked in the male all fractions contained higher proportions of i8-muricholate and lower percentages of chenodeoxycholate in the female larger amounts of deoxycholate and cholate appeared in cytosol, and greater quantities of lithocholate were found in cytosol and mitochondria. An increase of hepatic y8-muricholate from Q% in normal male rats to 72% of the bile acids after 8-10 days of bile duct ligation has been reported [12], The concentration of hepatic bile acids in neonatal rats (0-1 to 60 days) increased after birth with a concomitant increase in chenodeoxycholate and )8-muricholate and a decrease in cholate until the 60th day of life [13]. 

In normal human liver (7 samples) identified bile acids were cholate (54%), chenodeoxycholate (28%), and deoxycholate (18%) [12]. With a more sensitive system of analysis (glass capillary gas chromatography-mass spectrometry and selected ion monitoring) the values reported for 5 bile acids from 10 samples of normal human bile [14] were cholate (41%), chenodeoxycholate (39%), deoxycholate (15%), ursodeoxycholate (4%), and lithocholate (1%). 

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M. C. Carey, in Enterohepatic Circulation of Bile Acids and Sterol Metabolism, G. Paumgartner, ed., MTP Press, Lancaster, Boston, 1984. 

Phenolphthaleia is a cathartic dmg and the basis of many OTC laxatives. Its action is mainly on the colon to produce a soft semifluid stool within six to eight hours. Its action may persist for several days owiag to enterohepatic circulation and it may cause red urine if urine is alkaline. 

Approximately 0.05 to 0.2% of vitamin > 2 stores are turned over daily, amounting to 0.5—8.0 )J.g, depending on the body pool size. The half-life of the body pool is estimated to be between 480 and 1360 days with a daily loss of vitamin > 2 of about 1 )J.g. Consequentiy, the daily minimum requirement for vitamin B22 is 1 fig. Three micrograms (3.0 J.g) vitamin B22 are excreted in the bile each day, but an efficient enterohepatic circulation salvages the vitamin from the bile and other intestinal secretions. This effective recycling of the vitamin contributes to the long half-life. Absence of the intrinsic factor intermpts the enterohepatic circulation. Vitamin > 2 is not catabolized by the body and is, therefore, excreted unchanged. About one-half of the vitamin is excreted in the urine and the other half in the bile. 

Dmgs, such as opiates, may undergo metabolism both in the intestinal wall and in the fiver (first-pass metabolism). The metabolism may be extensive and considerably reduce the amount of dmg reaching the systemic circulation. Alternatively, the metabolite may be metabofically active and contribute significantly to the action of the parent dmg. Some compounds undergo enterohepatic circulation in which they are secreted into the GI tract in the bile and are subsequently reabsorbed. Enterohepatic circulation prolongs the half-life of a dmg. 

Houten SM, Auwerx J (2004) The enterohepatic nuclear receptors are major regulators of the enterohepatic circulation of bile salts. Ann Med 36 482-491... 

The only relevant information located was that administration of cholestyramine resin may increase fecal excretion of endosulfan trapped in the enterohepatic circulation (Dreisbach and Robertson 1987 Howland 1990 HSDB 1999). 

Enterohepatic circulation can lead to toxic effects. For example, the drug chloramphenicol is metabolized to a conjugate that is excreted in bile by the rat. Once in the gut, the conjugate is broken down to release a phase 1 metabolite that undergoes further metabolism to yield toxic products. When these are reabsorbed, they can cause toxicity. The rabbit, by contrast, excretes chloramphenicol conjugates in urine, and there are no toxic effects at the dose rates in question. 

Most Bile Acids Return to the Liver in the Enterohepatic Circulation... 

Although products of fat digestion, including cholesterol, are absorbed in the first 100 cm of small intestine, the primary and secondary bile acids are absorbed almost exclusively in the ileum, and 98—99% are returned to the liver via the portal circulation. This is known as the enterohepatic circulation (Figure 26—6). However, lithocholic acid, because of its insolubility, is not reabsorbed to any significant extent. Only a small fraction of the bile salts escapes absorption and is therefore eliminated in the feces. Nonetheless, this represents a major pathway for the elimination of cholesterol. Each day the small pool of bile acids (about 3-5 g) is cycled through the intestine six to ten times and an amount of bile acid equivalent to that lost in the feces is synthesized from cholesterol, so that a pool of bile acids of constant size is maintained. This is accomplished by a system of feedback controls. 

A small but variable proportion of the carotenoids with one or two P-ionone rings (mainly P-carotene) are cleaved in the enterocytes to produce retinol (vitamin A). This process is very tightly controlled, so that too much vitamin A is not produced, although the control mechanism is not clear. Some cleavage of P-carotene can also occur in the liver, but this does not account for the turnover of P-carotene in the body. Small amounts of carotenoids are subject to enterohepatic circulation, but this does not account for losses. 

Experiments with rats given oral doses of tritiated food-grade mineral oil provide supporting evidence that the absorption of hydrocarbons in mineral oils is limited. Five hours after dosing with 0.66 mL/kg of tritiated mineral oil ("liquid petrolatum U.S.P."), -75% of the administered radioactivity remained in the alimentary tract, and only 3% of the administered radioactivity was accounted for by radioactivity in other parts of the rat carcass (Ebert et al. 1966). About 80% of the administered radioactivity was recovered in feces during the first 2 days after treatment, and over 90% of the radioactivity in the feces was in the form of mineral oil. These data are consistent with the hypothesis that ingested mineral oil was poorly absorbed. Neither biliary excretion nor enterohepatic circulation of mineral oils was measured in this study, and thus, any quantitative estimates of the extent of absorption based on these data should be viewed as tentative. 

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. 

Small, D. M. Point mutations in the ileal bile salt transporter cause leaks in the enterohepatic circulation leading to severe chronic diarrhea and malabsorption. J. Clin. Invest. 1997,... 

Ohzawa et al [112] studied the absorption, distribution, and excretion of 14C miconazole in rats after a single administration. After the intravenous administration of 14C miconazole at a dose of 10 mg/kg to the male rats, the plasma concentration of radioactivity declined biophysically with half-lives of 0.76 h (a phase) and 10.32 h (/ phase). After oral administration of 14C miconazole at a dose of 1, 3, or 10 mg/kg to male rats, the plasma concentration of radioactivity reached the maximum level within 1.25 h, after dosing and the decline of radioactivity after the maximum level was similar to that after intravenous administration. At a dose of 30 mg/kg, the pharmacokinetic profile of radioactivity in the plasma was different from that at the lower doses. In the female rats, the plasma concentration of radioactivity declined more slowly than that in male rats. The tests were conducted on pregnant rats, lactating rats, bile-duct cumulated male rats. Enterohepatic circulation was observed. In the in situ experiment, 14C miconazole injected was observed from the duodenum, jejunum, and/or ileum, but not from the stomach. 

Grundy SM, Ahrens EH, Jr., Salen G. Interruption of the enterohepatic circulation of bile acids in man comparative ef-... 

Lepercq P., Hermier D., David O., Michelin R., Gibard C., Beguet F., Relano, P., Cavuela C. and Juste C. (2005). Increasing ursodeoxycholic acid in the enterohepatic circulation of pigs through the administration of living bacteria . Br J Nutr, 93(4), 457 -69. 

Animal studies indicate that the pathogenesis of NSAID small intestinal toxicity involves multiple interactions dependent on enterohepatic circulation, epithelial permeability, neutrophil infiltration and bacterial infection [233]. Several investigations [234-238] have suggested that bacterial flora may play a role in the pathogenesis of NSAID bowel injury and Robert and Asano [239] did show more than 25 years ago that germ-free rats are resis-... 

The primary action of BARs is to bind bile acids in the intestinal lumen, with a concurrent interruption of enterohepatic circulation of bile acids, which decreases the bile acid pool size and stimulates hepatic synthesis of bile acids from cholesterol. Depletion of the hepatic pool of cholesterol results in an increase in cholesterol biosynthesis and an increase in the... 

The metabolites and metabolic pathway of a new anticonvulsant drug, sodium valproate, in rats were investigated using carbon-14 labeled sodium valproate. Most of the metabolites in urine and bile were a glucuronide conjugate of valproic acid. Free sodium valproate was as little as one-seventh of the total metabolites. In feces, only free sodium valproate was detected, and the possibility of enterohepatic circulation of sodium valproate was presumed. A part of dosed sodium valproate was excreted in expired air in the form of CO2. This degradative reaction took place in liter mitochondria and required CoA and oxygen. It was stimulated by ATP... 

Wang, Y.M. and Reuning, R. (1994). A comparison of two surgical techniques for the preparation of rats with chronic hile duct canulae for the investigation of enterohepatic circulation. Lab. Anim. Sci. 44 479 485. 

Effects of Interrupted Enterohepatic Circulation on Biliary and Urinary Handling of Phenol Red... 

The excretion of chloroform and its metabolites is understood, based on human and animal data derived from oral and inhalation studies (Brown et al. 1974a Corley et al. 1990 Fry et al. 1972 Taylor et al. 1974). The major route of chloroform elimination is pulmonary, but minor pathways are through enterohepatic circulation, urine, and feces as parent compound or metabolites. There are no human or animal data regarding excretion of dermally applied chloroform. 

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