Biotransformation to metabolite

Most drugs are not excreted unchanged by the kidneys but first are biotransformed to metabolites that then are excreted. Renal failure not only may retard the excretion of these metabolites, which in some cases have important pharmacologic activity, but, in some cases, alters the nonrenal as well as the renal metabolic clearance of drugs (15, 24). The impact of impaired renal function on drug metabolism is dependent on the metabolic pathway, as indicated in Table 5.2. In most... 

Ciccoli and coworkers have shown that incubation of rat erythrocytes with hydroxy lated metabolites of aniline, dapsone (39) and the corresponding hydroxylamines brings about enhanced release of iron and methemoglobin formation. This did not occur with parent compounds. That xenobiotics are effective only after biotransformation to metabolites in vivo is supported by acute intoxication of rats with aniline or 39 and marked increase in the erythrocyte content of free iron and of methemoglobin144. The potent toxicity of aniline-derived aminophenylnorharman in the liver of the gpt delta transgenic mouse has been demonstrated145,146. 

Direct evidence for accumulation of PAHs by species that are able to metabolize these compounds is often difficult to obtain because of the rapid rate of biotransformation to metabolites that are not routinely detected by standard analytical techniques. If appreciable metabolism is occurring, then the bioaccumulation study needs to be performed using radiolabeled compounds to allow a mass-balance accounting of parent compounds and metabolites. Hence, for metabolically active species that accumulate very little parent compound, it may be more appropriate to monitor the metabolic products for evidence of accumulation. Two techniques have been developed to measure PAH metabolites one utilizes HPLC fluorescence detection of metabolites in bile of teleosts and the other uses P-postlabeling for DNA adducts that occur as a result of the interaction of metabolites and cellular DNA. Both techniques have displayed a highly positive correlation with environmental concentrations, making them useful for monitoring populations in our coastal areas. 

The kinetic properties of chemical compounds include their absorption and distribution in the body, theit biotransformation to more soluble forms through metabolic processes in the liver and other metabolic organs, and the excretion of the metabolites in the urine, the bile, the exhaled air, and in the saliva. An important issue in toxicokinetics deals with the formation of reactive toxic intermediates during phase I metabolic reactions (see. Section 5.3.3). 

Table 1 also indicates that some FMs, including the PCMs and NMs, do not pass ready or inherent biodegradation tests. However, this does not mean that these FMs do not undergo biotransformation to polar metabolites under realistic conditions. These realistic biodegradation tests may be conducted in vitro, in bench-top die-away studies, or as continuous activated sludge and porous pot tests. Ideally, the conditions should include (1) realistic FM concentrations... 

The selective lampricide, 3-trif1uoromethy1-4-nitrophenol (TFM), is used to control the sea lamprey (Petromyzon marinus) in the Great Lakes (12, 13). Recent studies have shown that in rats TFM is primarily biotransformed to reduced TFM (14). The major metabolite (Figure 1) found in rainbow trout (Salmo gaivdnevi), however, was the glucuronide conjugate of TFM (IS, 16). 

It causes antiemetic action by blocking dopamine (D receptors and it also increases gastric motility. It is absorbed orally but bioavailability is 15% due to first pass metabolism. It is completely biotransformed and metabolites are excreted in urine. It is used in nausea and vomiting in postoperative period, drug induced, radiation, uraemia, hepatitis, peptic ulcer. It is also useful in reflex oesophagitis. 

In humans, bupropion undergoes extensive biotransformation to three metabolites that have pharmacological activity ( 469). During treatment, these metabolites accumulate in concentrations several times higher than the parent compound (352). High plasma levels of these metabolites, particularly hydroxybupropion, may be associated with an increased incidence of serious adverse effects, as well as poorer antidepressant response ( 314). These observations form the basis of the possible utility of using TDM to guide dose adjustment with bupropion. 

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. 

These drugs include alcohols (ethchlorvynol, chloral hydrate), piperidinediones (glutethimide, methyprylon), and carbamates (meprobamate). They are rarely used in therapy, though the low cost of chloral hydrate makes it attractive for institutional use. Little is known about their molecular mechanisms of action. Most of these drugs are biotransformed to more water-soluble compounds by hepatic enzymes. Trichloroethanol is the pharmacologically active metabolite of chloral hydrate and has a half-life of 6-10 hours. However, its toxic metabolite, trichloroacetic acid, is cleared very slowly and can accumulate with the nightly administration of chloral hydrate. 

Chemical inhibition, which involves an evaluation of the effects of known CYP enzyme inhibitors on the metabolism of a drug candidate by human liver microsomes. Chemical inhibitors of CYP must be used cautiously because most of them can inhibit more than one CYP enzyme and some chemicals can inhibit one enzyme but activate another. Some chemical inhibitors are mechanism-based inhibitors that require biotransformation to a metabolite that inhibits or inactivates CYP. 

The lipophilicity of the drug candidate is informative because drag candidates with a log D7 4 greater than 1 are likely to require biotransformation to more polar metabolites to facilitate their elimination in urine or bile. The chemical structure of the drug candidate provides important information on the potential for enzymes other than CYP to be involved in its metabolism. Table 9 shows a variety... 

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