Approaches for Minimizing Metabolic Activation of New Drug Candidates in Drug Discovery

  • Sanjeev KumarEmail author
  • Kaushik Mitra
  • Kelem Kassahun
  • Thomas A. Baillie
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 196)


A large body of circumstantial evidence suggests that metabolic activation of drug candidates to chemically reactive electrophilic metabolites that are capable of covalently modifying cellular macromolecules may result in acute and/or immune system-mediated idiosyncratic toxicities in humans. Thus, minimizing the potential for metabolic activation of new drug candidates during the drug discovery and lead optimization stage represents a prudent strategy to help discover and develop the next generation of safe and effective therapeutic agents. In the present chapter, we discuss the scientific methodologies that currently are available to industrial pharmaceutical scientists for assessing and minimizing metabolic activation during drug discovery, their attributes and limitations, and future scientific directions that have the potential to help advance progress in this field. We also propose a roadmap that should help utilize the armamentarium of available scientific tools in a logical way and contribute to addressing metabolic activation issues in the drug discovery-setting in a rapid, scientifically appropriate, and resource-conscious manner.


Metabolic activation Bioactivation Reactive intermediates Covalent binding Drug discovery 





Potassium cyanide







The authors would like to thank Drs. Alana Upthagrove and Timothy Schultz-Utermoehl for some of the studies discussed in this chapter.


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Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  • Sanjeev Kumar
    • 1
    Email author
  • Kaushik Mitra
  • Kelem Kassahun
  • Thomas A. Baillie
  1. 1.Department of Drug Metabolism and PharmacokineticsMerck Research LaboratoriesRahwayUSA

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