Mechanisms of drug toxicity and relevance to pharmaceutical development

Drug Metab Pharmacokinet. 2011;26(1):3-14. doi: 10.2133/dmpk.dmpk-10-rv-062. Epub 2010 Oct 22.


Toxicity has been estimated to be responsible for the attrition of approximately one-third of drug candidates and is a major contributor to the high cost of drug development, particularly when not recognized until late in clinical trials or post-marketing. The causes of drug toxicity can be classified in several ways and include mechanism-based (on-target) toxicity, immune hypersensitivity, off-target toxicity, and bioactivation/covalent modification. In addition, idiosyncratic responses are rare but can be one of the most problematic issues; several hypotheses for these have been advanced. Although covalent binding of drugs to proteins was described almost 40 years ago, the significance to toxicity has been difficult to establish; recent literature in this field is considered. The development of more useful biomarkers and short-term assays for rapid screening of drug toxicity early in the drug discovery/development process is a major goal, and some progress has been made using "omics" approaches.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Biotransformation
  • Chemical and Drug Induced Liver Injury
  • Cytochrome P-450 Enzyme System / metabolism
  • Drug Discovery*
  • Drug Evaluation, Preclinical
  • Drug Hypersensitivity
  • Drug-Related Side Effects and Adverse Reactions*
  • Haptens / immunology
  • Humans
  • Liver / drug effects
  • Models, Animal
  • Pharmaceutical Preparations / metabolism*
  • Protein Binding
  • Proteomics
  • Safety-Based Drug Withdrawals
  • Toxicogenetics


  • Biomarkers
  • Haptens
  • Pharmaceutical Preparations
  • Cytochrome P-450 Enzyme System