Managing the challenge of chemically reactive metabolites in drug development.

TitleManaging the challenge of chemically reactive metabolites in drug development.
Publication TypeJournal Article
Year of Publication2011
AuthorsPark KB, Boobis A, Clarke S, Goldring CEP, Jones D, Kenna GJ, Lambert C, Laverty HG, Naisbitt DJ, Nelson S, Nicoll-Griffith DA, Obach SR, Routledge P, Smith DA, Tweedie DJ, Vermeulen N, Williams DP, Wilson ID, Baillie TA
JournalNat Rev Drug Discov
Volume10
Issue4
Pagination292-306
Date Published2011 Apr
ISSN1474-1784
KeywordsAnimals, Drug Design, Drug Discovery, Drug Industry, Humans, Pharmaceutical Preparations, Risk Assessment, Risk Management
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.

DOI10.1038/nrd3408
Alternate JournalNat Rev Drug Discov
PubMed ID21455238