title: Screening for reactive intermediates and toxicity assessment in drug discovery.
abstract: Moving forward in the 21st century, toxicity remains a significant cause for failures during drug development, and limited correlations exist between preclinical in vitro cellular toxicity and/or in vivo animal toxicity models, and human toxicity. This is due, in part, to the fact that drug candidates generally target multiple tissues rather than single organs, and result in a series of inter-related biochemical events. Drug-induced toxicities, such as idiosyncratic drug reactions, represent a serious complication of drug therapy that needs to be addressed at the drug discovery stage. Many robust toxicity screening methods, however, have been developed, and are described in the literature. Although biochemical mechanisms of drug-induced toxicities are complex, by combining these screening methods into a panel of assays, a risk assessment profile/decision-making guide can be obtained for each drug candidate. The panel of assays covered by this review broadly includes in silico prediction of reactive intermediates, detection and structural characterization of reactive intermediates, covalent binding of reactive intermediates to macromolecules, and the impact of reactive intermediates on cellular functions. Current and future strategies for the proper sequencing of these assays in a drug discovery environment are also discussed.
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development LLC, Drug Discovery, Spring House, PA 19477, USA. gcaldwel@prdus.jnj.com
authors.forename: Gary W
authors.initials: GW
authors.lastname: Caldwell
authors.forename: Zhengyin
authors.initials: Z
authors.lastname: Yan
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003198:Computer Simulation; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D018736:DNA Adducts / Q000378:metabolism; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions / Q000209:etiology* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000032:analysis; D005609:Free Radicals / Q000032:analysis; D006801:Humans; D008107:Liver Diseases / Q000209:etiology; D020714:Maximum Tolerated Dose; D008862:Microsomes, Liver / Q000187:drug effects
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D018736:DNA Adducts; D004791:Enzyme Inhibitors; D005609:Free Radicals; D003577:Cytochrome P-450 Enzyme System