Unique/major human metabolites: why, how, and when to test for safety in animals

Drug Metab Rev. 2008;40(3):447-63. doi: 10.1080/03602530802186561.


A Draft Guidance for Industry on "Safety Testing of Drug Metabolites" was released by FDA in 2005. According to these recommendations, there may be instances when the safety profile of human metabolites may mandate their direct safety testing in animals prior to registration and approval of new molecular entity. In response to this evolving regulatory environment, pragmatic and scientifically driven approaches should be used to assess which (if any) metabolites may require direct safety testing in animals. A specific Lilly case study highlights a strategic approach for evaluation of unique and major human metabolites of a drug in Phase 2 development.

Publication types

  • Review

MeSH terms

  • Animals
  • Biotransformation
  • Clinical Trials as Topic* / legislation & jurisprudence
  • Clinical Trials, Phase I as Topic
  • Clinical Trials, Phase II as Topic
  • Clinical Trials, Phase III as Topic
  • Drug Approval
  • Drug Evaluation, Preclinical*
  • Drugs, Investigational / pharmacokinetics*
  • Drugs, Investigational / toxicity
  • Government Regulation
  • Guidelines as Topic
  • Humans
  • Risk Assessment
  • Toxicity Tests*
  • United States
  • United States Food and Drug Administration


  • Drugs, Investigational