Role of Covalent Binding in Drug Toxicity

With the exception of some anticancer drugs, chemicals directly toxic to tissues are eliminated in the drug development process, so drug toxicity involving covalent binding usually is mediated by chemically reactive metabolites. Current mechanistic understanding of these toxic reactions usually extends to identification of the reactive metabolite and metabolic pathway involved. In some cases, protective mechanisms for 

FIGURE 16.4 General scheme for the role played by reactive drug metabolites in causing a variety of adverse reactions. The reactive metabolites usually account for only a small fraction of total drug metabolism and are too unstable to be chemically isolated and analyzed. In many cases, covalent binding of these metabolites to tissue macromolecules only occurs after their formation exceeds a critical threshold that overcomes host detoxification and repair mechanisms. 

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