title: Predicting toxicities of reactive metabolite-positive drug candidates.
abstract: Because of the inability to predict and quantify the risk of idiosyncratic adverse drug reactions (IADRs) and because reactive metabolites (RMs) are thought to be responsible for the pathogenesis of some IADRs, the potential for RM formation within new chemical entities is routinely examined with the ultimate goal of eliminating or reducing the liability through iterative design. Likewise, avoidance of structural alerts is almost a standard practice in drug design. However, the perceived safety concerns associated with the use of structural alerts and/or RM screening tools as standalone predictors of toxicity risks may be overexaggerated. Numerous marketed drugs form RMs but do not cause idiosyncratic toxicity. In this review article, we present a critique of the structural alert/RM concept as applied in drug discovery and evaluate the evidence linking structural alerts and RMs to observed toxic effects. Pragmatic risk mitigation strategies to aid the advancement of drug candidates that carry a RM liability are also discussed.
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism Department, Pfizer Worldwide Research and Development, 1Cambridge, Massachusetts 02139 and.
authors.forename: Amit S
authors.initials: AS
authors.lastname: Kalgutkar
authors.forename: Deepak
authors.initials: D
authors.lastname: Dalvie
mesh_terms: D000818:Animals; D001711:Biotransformation; D055808:Drug Discovery / Q000379:methods*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000209:etiology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D061214:Patient Safety; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D018570:Risk Assessment; D012307:Risk Factors; D013329:Structure-Activity Relationship; D066007:Toxicokinetics; D014116:Toxicology / Q000379:methods*
chemical_list: D004364:Pharmaceutical Preparations
keywords: ADRs; adverse drug reactions; bioactivation; covalent binding; cytochrome P450; electrophile; glutathione; hepatotoxicity; idiosyncratic; liver microsomes; precision medicine; prediction in pharmacology; structural alert