title: On mechanisms of reactive metabolite formation from drugs.
abstract: Idiosyncratic adverse drug reactions (IADRs) cause a broad range of clinically severe conditions of which drug induced liver injury (DILI) in particular is one of the most frequent causes of safety-related drug withdrawals. The underlying cause is almost invariably formation of reactive metabolites (RM) which by attacking macromolecules induc eorgan injuries. Attempts are being made in the pharmaceutical industry to lower the risk of selecting unfit compounds as clinical candidates. Approaches vary but do not seem to be overly successful at the initial design/synthesis stage. We review here the most frequent categories of mechanisms for RM formation and propose that many cases of RMs encountered within early ADME screening can be foreseen by applying chemical and metabolic knowledge. We also mention a web tool, SpotRM, which can be used for efficient look-up and learning about drugs that have recognized IADRs likely caused by RM formation.
authors.affiliation: Awametox Consulting, Lilldalsvagen 17 A, SE-144 61 Rönninge, Sweden. alf.cl@telia.com
authors.forename: Alf
authors.initials: A
authors.lastname: Claesson
authors.forename: Ola
authors.initials: O
authors.lastname: Spjuth
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects / Q000378:metabolism; D002264:Carboxylic Acids / Q000009:adverse effects / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D006846:Hydrocarbons, Halogenated / Q000009:adverse effects / Q000378:metabolism; D020407:Internet; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011809:Quinones / Q000009:adverse effects / Q000378:metabolism; D057386:Search Engine
chemical_list: D002264:Carboxylic Acids; D006846:Hydrocarbons, Halogenated; D004364:Pharmaceutical Preparations; D011809:Quinones; D000082:Acetaminophen; D003577:Cytochrome P-450 Enzyme System