title: Reactive Metabolites: Current and Emerging Risk and Hazard Assessments.
abstract: Although idiosyncratic adverse drug reactions are rare, they are still a major concern to patient safety. Reactive metabolites are widely accepted as playing a pivotal role in the pathogenesis of idiosyncratic adverse drug reactions. While there are today well established strategies for the risk assessment of stable metabolites within the pharmaceutical industry, there is still no consensus on reactive metabolite risk assessment strategies. This is due to the complexity of the mechanisms of these toxicities as well as the difficulty in identifying and quantifying short-lived reactive intermediates such as reactive metabolites. In this review, reactive metabolite risk and hazard assessment approaches are discussed, and their pros and cons highlighted. We also discuss the nature of idiosyncratic adverse drug reactions, using acetaminophen and nefazodone to exemplify the complexity of the underlying mechanisms of reactive metabolite mediated hepatotoxicity. One of the key gaps moving forward is our understanding of and ability to predict the contribution of immune activation in idiosyncratic adverse drug reactions. Sections are included on the clinical phenotypes of immune mediated idiosyncratic adverse drug reactions and on the present understanding of immune activation by reactive metabolites. The advances being made in microphysiological systems have a great potential to transform our ability to risk assess reactive metabolites, and an overview of the key components of these systems is presented. Finally, the potential impact of systems pharmacology approaches in reactive metabolite risk assessments is highlighted.
authors.affiliation: DMPK, Respiratory, Inflammation & Autoimmunity iMed, AstraZeneca R&D , 431 83 Mölndal, Sweden.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Thompson
authors.affiliation: DMPK, Cardiovascular & Metabolic Diseases iMed, AstraZeneca R&D , 431 83 Mölndal, Sweden.
authors.forename: Emre M
authors.initials: EM
authors.lastname: Isin
authors.affiliation: Translational Safety, Drug Safety and Metabolism, AstraZeneca R&D , Darwin Building 310, Cambridge Science Park, Milton Rd, Cambridge CB4 0FZ, United Kingdom.
authors.forename: Monday O
authors.initials: MO
authors.lastname: Ogese
authors.affiliation: Translational Safety, Drug Safety and Metabolism, AstraZeneca R&D , 35 Gatehouse Dr, Waltham, Massachusetts 02451, United States.
authors.forename: Jerome T
authors.initials: JT
authors.lastname: Mettetal
authors.affiliation: Translational Safety, Drug Safety and Metabolism, AstraZeneca R&D , Darwin Building 310, Cambridge Science Park, Milton Rd, Cambridge CB4 0FZ, United Kingdom.
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Williams
mesh_terms: D000082:Acetaminophen / Q000378:metabolism / Q000633:toxicity; D018712:Analgesics, Non-Narcotic / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000378:metabolism / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury / Q000175:diagnosis / Q000378:metabolism; D004342:Drug Hypersensitivity / Q000175:diagnosis / Q000378:metabolism; D064420:Drug-Related Side Effects and Adverse Reactions / Q000175:diagnosis / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010879:Piperazines; D018570:Risk Assessment / Q000379:methods; D014230:Triazoles / Q000378:metabolism / Q000633:toxicity
chemical_list: D018712:Analgesics, Non-Narcotic; D018687:Antidepressive Agents, Second-Generation; D004364:Pharmaceutical Preparations; D010879:Piperazines; D014230:Triazoles; D000082:Acetaminophen; C051752:nefazodone