Enterohepatic recirculation

Cholestyramine, a chelating agent, binds chlordecone present in the gastrointestinal tract and limits its enterohepatic recirculation (Boylan et al. 1978 Cohn et al. 1978). This interaction leads to increased excretion of the chlordecone and decreased toxicity. Thus, persons being treated with cholestyramine to lower plasma cholesterol may experience increased excretion of chlordecone and decreased toxicity. The use of cholestyramine as a therapeutic agent in cases of chlordecone poisoning is discussed more fully in Section 2.8.2, Reducing Body Burden. 

Chlordecone, which is excreted mainly in the feces, appears to undergo enterohepatic recirculation, which limits its excretion (Boylan et al. 1978). Analysis of the amount of chlordecone excreted in the bile compared to the amount found in the stool has indicated that only 5-10% of the bile level of the pesticide is eliminated in the feces (Boylan et al. 1978). Approximately equal fractions of... 

Like most halogenated hydrocarbon pesticides, very little of the chlordecone or its metabolites is excreted via the urine. Because of the apparent enterohepatic recirculation of chlordecone and chlordecone alcohol, most experimental approaches to chlordecone detoxification have focused on limiting reabsorption from the gastrointestinal tract using cholestyramine (Boylan et al. 1978 Cohn et al. 1978), liquid paraffin (Richter et al. 1979), and chlorella and chlorella- derived sporopollenin (Pore 1984). No information was found that indicated that mirex undergoes enterohepatic recirculation, so it is not known whether use of these therapies would be effective in reducing absorption of mirex. 

Two other compounds have been examined for therapeutic action in animal (rat) models of chlordecone poisoning. Sporopollenin, a carotenoid polymer derived from the cell walls of the alga Chlorella prothecoides, was reported to bind to chlordecone (Pore 1984). In animal studies using rats, sporopollenin decreased the half life of chlordecone from 40 days to 19 days. The excretion rate in control animals fed a-cellulose, in the same bulk amount as sporopollenin, did not change. Prevention of enterohepatic recirculation of chlordecone was also evaluated with liquid paraffin. 

In a second study (Walton et al. 2001b), the magnitude of the interspecies differences in the internal dose of compounds for which glucuronidation is the major pathway of metabolism in either humans or in the test species was determined. There were major interspecies differences in the nature of the biological processes that influence the internal dose including route of metabolism, the extent of pre-systemic metabohsm, and enterohepatic recirculation. There was also a wide variability in the magnitude of differences in the internal dose for all of the test species. The mean values for the clearance ratios compared to humans were 4.5 for the mouse, 9.1 for the rat, 8.7 for the rabbit, and 9.7 for the dog. Thus, the fourfold default factor was exceeded for aU the species. 

This synthetic benzamide was studied in two different schedules, with the daily schedule exceeding MTD at first dose-level of 2 mg/m, unpredicted, possibly due to long ti/2 from possible enterohepatic recirculation. The fortnightly schedule was found to be feasible, and an MTD of 10 mg/m has been established from 28 patients [133]. There were no cUnically significant cardiac toxicities either from a rhythm perspective or from assessment of left ventricular ejection fraction. Toxicities seen include anorexia, nausea, vomiting, diarrhea, fatigue, myelosuppression, hypoalbiuninemia and hypophospho-temia. 

Estrogens - Ethinyl estradiol is rapidly absorbed with peak concentrations attained in 1 to 2 hours. It undergoes considerable first-pass elimination. Mestranol is demethylated to ethinyl estradiol. Ethinyl estradiol is approximately 97% to 98% bound to plasma albumin. Half-life varies from 6 to 20 hours. It is excreted in bile and urine as conjugates, and undergoes some enterohepatic recirculation. 

The main route of elimination is via hepatic excretion into bile some enterohepatic recirculation may occur. The drug has a very low plasma clearance with negligible renal excretion. Neither amiodarone nor its metabolite is dialyzable. 

There are no specific treatments for reducing the body burden following absorption of hexachlorobutadiene. As discussed in Section 2.3, there is extensive reabsorption and enterohepatic recirculation of biliary metabolites, which are thought to play a major role in the nephrotoxicity of the... 

Important limitations of the PBPK approach are realized for class 3 and 4 compounds with significant active distribution/absorption processes, where biliary elimination is a major component of the elimination process or where the assumptions of flow-limited distribution and well mixed compartments are not valid and permeability-limited distribution is apparent. These drawbacks could be addressed by the addition of permeability barriers for some tissues and by the incorporation of a more complex liver model which addresses active uptake into the liver, active efflux into the bile, biliary elimination and enterohepatic recirculation. However, this improvement to current methodologies requires the availability of the appropriate input data for quantification of the various processes involved as well as validation of the corresponding in vitro to in vivo scaling approaches. 

Most chelation and adsorption interactions can be circumvented by separating doses of the interacting drugs by a period of several hours, although note that this may not be wholly effective with drugs that undergo enterohepatic recirculation. 

It is readily absorbed orally. It is metabolized in the liver and undergoes enterohepatic recirculation. It is eliminated in faeces with a half-life of 5-7 days. Its most common adverse effects are hot flushes. 

Enterohepatic recirculation The reabsorption of drug and/or metabolites from the small bowel into the portal circulation after first pass metabolism has occurred. Such recirculation contributes to the total amount of drug and/or metabolites, which eventually enters the systemic circulation (e.g., demethylated and hydroxylated metabolites of tricyclic antidepressants). 

First-pass metabolism (first-pass effect) The passage of the drug from the portal circulation into hepatocytes and conversion there into metabolites. These metabolites may have a pharmacological profile different from that of the parent drug. They are typically then excreted by the hepatocytes into the biliary system and pass back into the small bowel where enterohepatic recirculation may occur (e.g., benzodiazepines, bupropion, nefazodone, neuroleptics, tricyclic antidepressants). 

Leflunomide is completely absorbed and has a mean plasma half-life of 19 days. A77-1726, the active metabolite of leflunomide, is thought to have approximately the same half-life and is subject to enterohepatic recirculation. Cholestyramine can enhance leflunomide excretion and increases total clearance by approximately 50%. 

Only 10-20% of orally administered sulfasalazine is absorbed, although a fraction undergoes enterohepatic recirculation into the bowel where it is reduced by intestinal bacteria to liberate sulfapyridine and 5-aminosalicylic acid (see Figure 62-8). Sulfapyridine is well absorbed while 5-aminosalicylic acid remains unabsorbed. Some sulfasalazine is excreted unchanged in the urine whereas sulfapyridine is excreted after hepatic acetylation and hydroxylation. Sulfasalazine s half-life is 6-17 hours. 

In dogs, absorption following oral administration tends to be poor. At similar oral doses, peak serum levels are lower and plasma levels are less persistent than those observed for methicillin. Following intramuscular administration, however, maximum concentrations in serum are reached within 30 min. In contrast to methicillin, liver is the main excretory pathway for nafcillin. Like most other penicillins, nafcillin undergoes biotransformation to a small extent. Parent compound and its metabolites are excreted in bile and urine. Concentrations of nafcillin in tissues tend to be higher and more persistent following parenteral administration than was the case for methicillin, obviously due to enterohepatic recirculation. 

Drug Interactions Acyclovir Antacids with magnesium and aluminum hydroxides Cholestyramine Drugs that alter gastrointestinal flora may interact with mycophenolate mofetil by disrupting enterohepatic recirculation Probenecid... 

Excretion is the elimination of the molecule from the organism by one of several routes. The urine is the major route, but expired air and bile may also be used. Urinary excretion involves filtration, passive diffusion, and active transport. Biliary excretion involves active transport, and there is a molecular weight threshold for compounds, above which excretion by this route becomes more important. Biliary excretion may lead to enterohepatic recirculation. Excretion by these routes can be saturated, leading to accumulation. 

---