Title:On Mechanisms of Reactive Metabolite Formation from Drugs
VOLUME: 13 ISSUE: 5
Author(s):Alf Claesson and Ola Spjuth
Affiliation:Awametox Consulting, Lilldalsvagen 17 A, SE-144 61 Ronninge, Sweden.
Keywords:Reactive metabolite, drug safety, hepatotoxicity, idiosyncratic adverse drug reaction, web application, structural
alerts, bioactivation
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 induce
organ 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.
