Mechanisms of drug toxicity and relevance to pharmaceutical development.

Guengerich FP
Drug Metab Pharmacokinet. 2011 26 (1): 3-14

PMID: 20978361 · PMCID: PMC4707670 · DOI:10.2133/dmpk.dmpk-10-rv-062

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.

MeSH Terms (18)

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

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