Reactive metabolites toxicology studies

Much is known about the biochemical toxicology of hepatotoxicants, yet much remains to be learned. Hepatotoxicity resulting in either cell necrosis, fibrosis, or fatty infiltration is known to be a widespread phenomenon, potentially of importance to human health. It is caused by numerous drugs and environmental agents, and its incidence is expected to increase as confounding viral liver disease becomes more prevalent. Much is known about mechanisms based upon comprehensive studies with a few prototypical chemicals—namely, CCb, ethanol and acetaminophen—which support a convergence of varied primary effects on the ultimate failure of mitochondrial function and Ca2+ homeostasis. The extensive metabolic activity of the liver exposes its cells to a continuous flux of prooxidants. The importance of metabolic activation for the production of reactive metabolites is well-... 

Madsen, K.G. et al. (2007) Development and evaluation of an electrochemical method for studying reactive phase-I metabolites correlation to in vitro drug metabolism. Chemical Research in Toxicology, 20 (5), 821-831. 

If a metabolite is pharmacologically active or structural alert (i.e., contains a reactive functional group, glutathione conjugates) then it should be considered for monitoring in toxicological and/or clinical studies. 

The true detoxification products as a rule appear in the urine, while the reactive intermediate toxic products remain in the body, tightly bound to tissue components, and thus chemically sequestered in the tissues. From the toxicological point of view therefore, it is not the percentage of the pharmacon and its metabolites recovered from urine, feces, and from the carcass by extraction that is most important in balance studies it is in fact the fraction of the... 

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