title: Managing the challenge of chemically reactive metabolites in drug development.
abstract: The normal metabolism of drugs can generate metabolites that have intrinsic chemical reactivity towards cellular molecules, and therefore have the potential to alter biological function and initiate serious adverse drug reactions. Here, we present an assessment of the current approaches used for the evaluation of chemically reactive metabolites. We also describe how these approaches are being used within the pharmaceutical industry to assess and minimize the potential of drug candidates to cause toxicity. At early stages of drug discovery, iteration between medicinal chemistry and drug metabolism can eliminate perceived reactive metabolite-mediated chemical liabilities without compromising pharmacological activity or the need for extensive safety evaluation beyond standard practices. In the future, reactive metabolite evaluation may also be useful during clinical development for improving clinical risk assessment and risk management. Currently, there remains a huge gap in our understanding of the basic mechanisms that underlie chemical stress-mediated adverse reactions in humans. This review summarizes our views on this complex topic, and includes insights into practices considered by the pharmaceutical industry.
authors: MRC Centre for Drug Safety Science, Division of Molecular & Clinical Pharmacology, The Institute of Translational Medicine, University of Liverpool, Liverpool L693GE, UK. B.K.Park@liverpool. ac.uk
authors: B Kevin
authors: BK
authors: Park
authors: Alan
authors: A
authors: Boobis
authors: Stephen
authors: S
authors: Clarke
authors: Chris E P
authors: CE
authors: Goldring
authors: David
authors: D
authors: Jones
authors: J Gerry
authors: JG
authors: Kenna
authors: Craig
authors: C
authors: Lambert
authors: Hugh G
authors: HG
authors: Laverty
authors: Dean J
authors: DJ
authors: Naisbitt
authors: Sidney
authors: S
authors: Nelson
authors: Deborah A
authors: DA
authors: Nicoll-Griffith
authors: R Scott
authors: RS
authors: Obach
authors: Philip
authors: P
authors: Routledge
authors: Dennis A
authors: DA
authors: Smith
authors: Donald J
authors: DJ
authors: Tweedie
authors: Nico
authors: N
authors: Vermeulen
authors: Dominic P
authors: DP
authors: Williams
authors: Ian D
authors: ID
authors: Wilson
authors: Thomas A
authors: TA
authors: Baillie
mesh_terms: D000818:Animals; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D004345:Drug Industry / Q000379:methods; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D018570:Risk Assessment / Q000379:methods; D012308:Risk Management / Q000379:methods
chemical_list: D004364:Pharmaceutical Preparations