Mechanisms of drug toxicity and relevance to pharmaceutical development.
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.
Department of Biochemistry and the Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA. f.guengerich@vanderbilt.edu
F Peter
FP
Guengerich
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001711:Biotransformation; D056486:Chemical and Drug Induced Liver Injury; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004342:Drug Hypersensitivity; D064420:Drug-Related Side Effects and Adverse Reactions; D006241:Haptens / Q000276:immunology; D006801:Humans; D008099:Liver / Q000187:drug effects; D023421:Models, Animal; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011485:Protein Binding; D040901:Proteomics; D056737:Safety-Based Drug Withdrawals; D043922:Toxicogenetics
D015415:Biomarkers; D006241:Haptens; D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System