On Mechanisms of Reactive Metabolite Formation from Drugs

Author(s): Alf Claesson, Ola Spjuth

Journal Name: Mini-Reviews in Medicinal Chemistry

Volume 13 , Issue 5 , 2013

Become EABM
Become Reviewer
Call for Editor


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.

Keywords: Reactive metabolite, drug safety, hepatotoxicity, idiosyncratic adverse drug reaction, web application, structural alerts, bioactivation

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2013
Published on: 12 March, 2013
Page: [720 - 729]
Pages: 10
DOI: 10.2174/1389557511313050009
Price: $65

Article Metrics

PDF: 63