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reactive drug metabolites

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Evidence Snippets

In this review, we present a critique of such reactive metabolites and evaluate the evidence linking them to observed toxic effects.
Evidence 1Source 1DOIPubMedprovenance

Supporting Sources

Linked Claims

Claim 1attrition driversupports2012Source 1DOIPubMed

Preclinical toxicity is presented as a major cause of drug discovery attrition and is frequently attributed to generation of protein-reactive drug metabolites.

Quoted textsource-backed
One of the main reasons for attrition is preclinical toxicity, frequently attributed to the generation of protein-reactive drug metabolites.
Claim 2drug discovery implicationsupports2012Source 1DOIPubMed

Reactive metabolite data can inform drug discovery through early detection of reactive metabolites and synthetic redesign to remove unfavorable functionality from candidates.

Quoted textsource-backed
Finally, we discuss the impact of such data on the drug discovery process, both through early detection of reactive metabolites and informed synthetic design, which eliminates unfavorable functionality from drug candidates.
Claim 3mechanistic risksupports2012Source 1DOIPubMed

Electrophilic metabolites can inhibit key metabolic enzymes and may lead to unfavorable drug-drug interactions.

Quoted textsource-backed
Next, we consider the inhibition of key metabolic enzymes by electrophilic metabolites, as well as unfavorable drug-drug interactions that may ensue.
Claim 4methodology progresssupports2012Source 1DOIPubMed

Methodology for characterization of reactive metabolites has advanced greatly in recent years.

Quoted textsource-backed
Methodology for the characterization of reactive metabolites has advanced greatly in recent years, and is summarized first.
Claim 5toxicity scopesupports2012Source 1DOIPubMed

Adverse drug reactions associated with reactive metabolites may include organ injury, especially liver injury, induced cellular processes, and hypersensitivity or allergic reactions possibly involving the immune system.

Quoted textsource-backed
Specific organ injury, particularly of the liver, is the most direct: we examine this in some detail. Moving to the cellular level, we also consider the upregulation of induced cellular processes. The related, but distinct, issue of hypersensitivity or allergic reactions to drugs and their metabolites, possibly via the immune system, is considered next.