title: Problems associated with in vitro assessment of drug inhibition of CYP3A4 and other P-450 enzymes and its impact on drug discovery.
abstract: The cytochromes P-450 recognize and metabolize a broad range of structurally diverse therapeutic agents. As a consequence, many clinically relevant drug--drug interactions (DDI) are associated with inhibition and/or induction of a specific P-450 enzymes (in particular human cytochrome P-450 3A4, CYP3A4). In addition to inhibition and induction, CYP-mediated drug metabolism may be enhanced upon coincubation with certain compounds. Moreover, some of these enzyme-based interactions appear to be substrate specific. In this presentation, several issues associated with the generation of accurate DDI information will be discussed.
authors.affiliation: Pharmacia Corporation, 301 Henrietta Street, 7265-300-319, Kalamazoo, MI 49007, USA. larry.c.winklers@pharmacia.com
authors.forename: L C
authors.initials: LC
authors.lastname: Wienkers
mesh_terms: D000465:Algorithms; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human