Enterohepatic cycling circulation

Figure 35.11 Enterohepatic cycling. Some drugs can move from the blood circulation to the liver, into the bile, into the intestine, to the liver, and back into circulation. This cycling decreases the rate of drug excretion.

This conclusion must be considered tentative at present. The half-life of a bile acid refers to the interval from secretion by the liver to excretion in the feces. It cannot take into account the number of enterohepatic cycles undergone by a bile acid molecule before it is excreted. Presumably, it is the rate of the enterohepatic circulation of bile acids that controls the rate of bile acid biosynthesis (28), and we do not know at present what factor or factors determine the rate of excretion. In the experiments in which the enterohepatic circulation was interrupted by administering the ion exchanger, it may be postulated that synthesis was stimulated by partial removal of the bile acid pool the mechanism of this effect is not unequivocal since the circulation rate of the pool was not known. 

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. 

Part of the drug that enters the gut through the bile is eliminated via the feces or may be reabsorbed and then be excreted in the urine or returned to the gut through the bile. The latter cycle is called enterohepatic circulation because in this cycle the compounds may travel the route in progressively reducing amounts... 

In cases of chronic ingestion exposure, isodrin can accumulate in the adipose tissue, due to its lip-ophilicity. It is encouraging that a means of hastening the excretion of stored isodrin has been developed. This involves the use of anion exchange resin, cholestyramine, which, when given orally to patients, enhances fecal excretion of isodrin. The rationale for the use of cholestyramine relates to the biliary-enterohepatic circulation, which cycles isodrin hence, cholestyramine by binding the insecticide, interrupts the reabsorption phase and shifts the equilibrium from reabsorption and storage to fecal excretion. 

Fig. 1.10 The enterohepatic circulation. Some drugs or their glucuronida conjugates and certain endogenous substances enter this cycle of events. The enterohepatic circulation of a drug may contribute to its duration of action. The horse, unlike other domestic animal species, does not possess a gall bladder.

Another consequence of biliary excretion is that the compound comes into contact with the gut microflora. The bacteria may metabolize the compound and convert it into a more lipid soluble substance which can be reabsorbed from the intestine into the portal venous blood supply, and so return to the liver. This may lead to a cycling of the compound known as enterohepatic recirculation which may increase the toxicity (figure 3,32). If this situation occurs the plasma level profile may show peaks at various times corresponding to reabsorption rather than the smooth decline expected. If the compound is taken orally, and therefore is transported directly to the liver and is extensively excreted into the bile, it may be that none of the parent compound ever reaches the systemic circulation. Alternatively the gut microflora may metabolize the compound to a more toxic metabolite which could be reabsorbed and cause a systemic toxic effect. An example of this is afforded by the hepatocarcinogen 2,4-dinitrotoluene discussed in more detail in Chapter 5. Compounds taken orally may also come directly into contact with the gut bacteria. For example, the naturally occurring glycoside cycasin is hydrolysed to the potent carcinogen methy... 

---