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Chemically Reactive Versus Stable Drug Metabolites: Role in Adverse Drug Reactions

It has been appreciated for some time that drug metabolites may contribute to both the beneficial and adverse properties of therapeutic agents, although the underlying mechanisms of metabolite-induced toxicities have not always been clear. Studies over the past 40 years on the relationship between biotransformation and drug toxicity have implicated chemically reactive metabolites as mediators of many serious drug toxicities, whereas few examples exist where stable metabolites whose structures do not differ greatly from those of their respective parents appear to be involved. As a result, screens for metabolic activation are now incorporated routinely into lead optimization programs with the goal of providing rational approaches for the structural redesign of lead compounds to eliminate, or at least minimize, the propensity for reactive metabolite formation. In this chapter, specific examples are given of drug discovery programs that have benefited from this approach, and contemporary approaches to address regulatory guidance on stable Metabolites in Safety Testing (“MIST”) are discussed. Finally, some future directions in this field are highlighted stemming from rapid technical developments in bioanalysis, bioinformatics, genetics, in vitro and in vivo animal models, and in silico tools to both understand and predict the roles of drug metabolites in adverse drug reactions.

Publication details

Print publication date
20 Nov 2015
Copyright year
Print ISBN
ePub eISBN
From the book series:
Drug Discovery