Bile, generally excretion

Some chemicals that strongly bind to biological receptors (ligands) can produce toxicity directly. However, most toxic chemicals are not intrinsically reactive and must be metabolized to reactive intermediates that often covalently bind to macromolecules (DNA, proteins, etc.), and, if present at a sufficient level, lead to toxicity. Metabolism generally serves to make lipophilic compounds more hydrophilic in order to facilitate excretion through the liver and into the bile for excretion into the feces or through the kidneys and into the urine. This process generally... 

It has been generally accepted, mainly on the basis of animal experiments (159,160), that the production of bile acids is increased in hyperthyroid and decreased in hypothyroid patients. Treatment of the latter subjects with thyroid hormones was actually shown to increase the turnover of cholic acid (161). The determination of fecal bile acids indicated, however, that bile acid elimination was inconsistently decreased in hypothyroid patients and that thyroid hormone therapy increased the bile acid excretion insignificantly (89,162). 

Clofibrate appears to have little general effect on bile acid metabolism, but, as Horlick et al. (25) have shown, it may affect bile acid excretion in certain types of hyperlipidemias. 

More significant is the risk of interorgan redistribution. Chelates forming in the hepatocyte may of course be transported into the bile and excreted in the feces. This is generally considered a positive attribute, but may simply reflect a limited ability to exit the cell. For instance, because ferrioxamine enters and exits cells with difficulty, almost all of the iron this agent removes from the body by biliary excretion (30%-50% of the total removed) originates in the hepatocyte (Hershko et al. 1978). Ferrioxamine that does make its way into the circulation from other sources is rapidly cleared by the kidney. On the one hand, this means that removal of iron... 

The newly born infant gut contents include a complex mixture of neutral and acidic steroids generally present as glycine and taurine conjugates or as sulphates[4]. The pattern of bile acids in meconium probably represents the accumulation of maternal and foetal products and is dominated by cholic acid, chenodeoxycholic acid, deoxycholic acid, lithocholic acid and hyocholic acid[5]. Epimeric, unsaturated or side-chain shortened bile acids have also been detected in meconium[6]. This bile acid profile is rapidly lost in infants and, at 18 months, the principle bile acids excreted are cholic acid and... 

Clofibrate - Space does not permit discussion of the many publications on this drug. Some of the more important ones dealt with effects on cholesterol synthesis, cholesterol and bile acid excretion, triglyceride synthesis, 3and effects on cell ultrastructure. For general information, two sources are recommended. ... 

There are several hypotheses to explain the NSP action on plasma cholesterol, including enhanced bile acid and neutral sterol excretion, the slowing of fat and cholesterol absorption and direct inhibition of hepatic cholesterol synthesis by propionate formed by large bowel fermentation of NSPs. Whole body cholesterol homoeostasis represents a balance between influx and loss. Cholesterol influx can come from dietary intake and de novo synthesis. Losses occur through the sloughing of epithelial cells and through the fecal excretion of nonabsorbed dietary cholesterol and biliary steroids (bile acids and neutral sterols). Bile acids are generally recovered in the ileum, and those that are not absorbed are excreted in the feces. Any increase in bile acid excretion leads to enhanced hepatic uptake of cholesterol and its conversion to bile acids with a consequent depletion of the plasma cholesterol pool. 

In phase 1 reactions, xenobiotics are generally converted to more polar, hydroxylated derivatives. In phase 2 reactions, these derivatives are conjugated with molecules such as glucuronic acid, sulfate, or glutathione. This renders them even more water-soluble, and they are eventually excreted in the urine or bile. 

Injection, inhalation, and dermal absorption generally result in the toxicant entering the bloodstream unaltered. Toxicants entering through ingestion are frequently modified or excreted in bile. 

Glickman et al. have also reported that PCP-glucuronide is excreted in the bile of rainbow trout exposed to PCP and penta-chloroanisole media(7). The biliary excretion after glucuronide conjugation must be one of general detoxification mechanisms for PCP in fish. 

Levels and detection frequency of TBBPA are generally lower than those of PBDEs and HBCDs in human samples. Consistent with its phenolic structure that can be rapidly conjugated in human hver and subsequently excreted in bile [36], TBBPA has a short human half-life that has been reported to be as low as 2 days in human plasma [28, 37]. In addition, HBCD and PBDEs are additive BERs, while TBBPA is a reactive BFR, meaning that TBBPA is chemically bound to the polymer structure and, thus, the leaching or release of TBBPA into the environment is limited [38]. Therefore, levels of TBBPA are often lower and detection of this... 

Many companies have tried to develop peptidic renin inhibitors. Unfortunately these are rather large molecules and not unexpectedly poor absorption was often observed. The role of physicochemical properties has been discussed for this class of compounds. One of the conclusions was that compounds with higher lipophilicity were better absorbed from the intestine [29]. Absorption and bile elimination rate are both MW-dependent. Lower MW results in better absorption and less bile excretion. The combined influence of molecular size and lipophilicity on absorption of a series of renin inhibitors can be seen from Figure 1.7. The observed iso-size curves are believed to be part of a general sigmoidal relationship between permeability and lipophilicity [30-31] (for further details see Chapter 3). 

Differences in clinical effectiveness are partly due to differences in absorption, distribution and excretion of the individual drugs. In general tetracyclines are absorbed irregularly from the gastrointestinal tract and part of the dose remains in the gut and is excreted in the faeces. However this part is able to modify the intestinal flora. Absorption of the more lipophilic tetracyclines, doxycycline and minocycline is higher and can reach 90-100%. The absorption is located in the upper small intestine and is better in the absence of food. Absorption is impaired by chelation with divalent cations. In blood 40-80% of tetracyclines is protein bound. Minocycline reaches very high concentrations in tears and saliva. Tetracyclines are excreted unchanged, in both the urine by passive filtration and in the feces. Tetracyclines are concentrated in the bile via an active... 

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