Role of Biotransformation Studies in Minimizing Metabolism-Related Liabilities in Drug Discovery
Journal Title: The AAPS Journal - Year 2008, Vol 10, Issue 1
Abstract
Metabolism-related liabilities continue to be a major cause of attrition for drug candidates in clinical development. Such problems may arise from the bioactivation of the parent compound to a reactive metabolite capable of modifying biological materials covalently or engaging in redox-cycling reactions leading to the formation of other toxicants. Alternatively, they may result from the formation of a major metabolite with systemic exposure and adverse pharmacological activity. To avert such problems, biotransformation studies are becoming increasingly important in guiding the refinement of a lead series during drug discovery and in characterizing lead candidates prior to clinical evaluation. This article provides an overview of the methods that are used to uncover metabolism-related liabilities in a pre-clinical setting and offers suggestions for reducing such liabilities via the modification of structural features that are used commonly in drug-like molecules.
Authors and Affiliations
Yue-Zhong Shu, Benjamin M. Johnson, Tian J. Yang
Keywords
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- EP ID EP681524
- DOI 10.1208/s12248-008-9016-9
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