Enterohepatic cycle

Drugs that are subject to enterohepatic cycling are, therefore, excreted slowly. Pertinent examples include digi-toxin and acidic nonsteroidal anti-inflammatory agents (p. 200). 

Amines may form N-glucuronides that, unlike 0-glucuronides, are resistant to bacterial p-glucuronidases. 

Soluble cytoplasmic sulfotrans-ferases conjugate activated sulfate (3 -phosphoadenine-5 -phosphosulfate) with alcohols and phenols. The conjugates are acids, as in the case of glucuronides. In this respect, they differ from conjugates formed by acetyltransfe-rases from activated acetate (acetyl-coenzyme A) and an alcohol or a phenol 

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When Reuben et al., measured the hourly secretion rates of phospholipids, bile acids and cholesterol in obese and nonobese individuals with and without cholesterol gallstone disease, they found that the pattern of results was quite different in the obese and the nonobese gallstone carriers. The obese had hypersecretion of cholesterol but normal bile-acid output, while the nonobese had normal cholesterol secretion but a reduced bile-acid output. The authors speculated that the most likely explanation for the high biliary cholesterol secretion rates in the obese was their increased total body cholesterol synthesis. Conversely, nonobese gallstone carriers often have a reduced total bile-acid pool size, and if the enterohepatic cycling frequency of this small bile-acid pool remains unchanged (controversial), it could explain the reduced bile-acid secretion rate seen in the normal weight (nonobese) individuals. 

CSF concentratons are less than 1% of plasma concentrations. Half-life ranged from 67 to 77.6 hours following the suspension. The long half-life is caused by presumed enterohepatic cycling and eventual fecal elimination. There is indirect evidence that atovaquone may undergo limited metabolism however, a specific metabolite has not been identified. 

Extensive enterohepatic cycling may be partly responsible for a drug s long persistence in the body. Orally administered activated charcoal and/or anion exchange resins have been used clinically to interrupt enterohepatic cycling and trap drugs in the gastrointestinal tract. 

Not recommended for those with severe renal and hepatic disease. E, enterohepatic cycling F, extensive first pass metabolism h, dosage adjustment may be necessary in patients with hepatic impairment H, dosage adjustment recommended for patients with hepatic impairment R, dosage adjustment necessary for patients with renal impairment. 

Sulindac is a sulfoxide prodrug. It is reversibly metabolized to the active sulfide metabolite, which is excreted in bile and then reabsorbed from the intestine. The enterohepatic cycling prolongs the duration of action to 12-16 hours. 

When chloramphenicol is administered parenterally, it rapidly enters the enterohepatic cycle, which is of significance because it prolongs the residence of the drug in the body. Deposition of chloramphenicol residues in animal tissues results from this prolongation of excretion. In diseased animals, residues of chloramphenicol can be detected for weeks after the initial administration. 

Strains of obligately anaerobic bacteria in rat (and human) intestinal microflora have been shown to produce iodothyronine glucuronidase and sulfatase activities [22,23]. This explains why T4 and T3 appear in feces of rats as free iodothyronines [24] although they are excreted in bile mainly as glucuronide conjugates. Recent studies indicate that a large fraction of T3G introduced in the rat intestinal tract is resorbed as free T3 liberated by bacterial hydrolysis [25,26]. In rats, therefore, glu-curonidation does not seem an irreversible pathway for the elimination of T4 and T3 but an essential step in the enterohepatic cycle of these compounds. 

Although in principle the metabolic clearance of plasma T3 may occur via several pathways, direct deiodination of the inner ring of T3 by the type I enzyme seems of minor importance (Section 2.2). Also, glucuronidation in the liver does not represent an irreversible pathway of T3 elimination since enzymatic hydrolysis of the conjugate in the intestine allows for the reabsorption of free T3 (enterohepatic cycle). Further, the finding that plasma T3 clearance is not affected in patients with liver cirrhosis [115] suggests that hepatic metabolism of T3 by sulfation and subsequent deiodination is less important than in rats. It appears, therefore, that the type III deiodinase of extrahepatic tissues is a major site for the clearance of plasma T3 as it is also for the production of plasma rT3. 

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