Covalent binding reactive metabolite studies

Utility of Reactive Metabolite Trapping and Covalent Binding Studies in Drug Discovery... 

While covalent binding studies have an advantage over the reactive metabolite assay in that they provide a quantitative estimate of covalently bound drug to proteins and therefore an indirect measure of reactive metabolite formation, there are no studies to date which show a correlation between the extent of covalent binding and/or reactive metabolite formed and the probability that a drug is... 

In the 1940s and 1950s the pioneering studies of James and Elizabeth Miller provided early evidence for in vivo conversion of chemical carcinogens to reactive metabolites. They found that reactive metabolites of the aminoazo dye A, /V-dimcthyl-4-aminoazobenzene (DAB), a hepatocarcinogen in rats, would bind covalently to proteins and nucleic acids. The term, metabolic activation, was coined by the Millers to describe this process. Moreover they demonstrated that covalent binding of these chemicals was an essential part of the carcinogenic process. 

Studies in recent years have revealed a number of remarkable drug interactions with irreversible or mechanism-based inhibitors of CYP3A, many of which can be attributed to inhibition of sequential intestinal and hepatic first-pass metabolism. Mechanism-based inhibition involves the metabolism of an inhibitor to a reactive metabolite, which either forms a slowly reversible metabolic-intermediate (MI) complex with the heme moiety or inactivates the enzyme irreversibly via covalent binding to the enzyme catalyzing the last step in the bioactivation sequence. As a result, mechanism-based inhibition is both... 

Administration of bromobcnzcnc to rats causes severe liver necrosis. Extensive in vivo and in vitro studies indicate that the liver damage results from the interaction of a chemically reactive metabolite, 4-bromobcnzcnc oxide, with hcpatocytcs. " Extensive covalent binding to hepatic tissue... 

ARE REACTIVE METABOLITE TRAPPING AND COVALENT BINDING STUDIES RELIABLE PREDICTORS OF TOXICITY POTENTIAL OF DRUG CANDIDATES ... 

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