Clinical and toxicological relevance of CYP2C9: drug-drug interactions and pharmacogenetics.
CYP2C9 is a major cytochrome P450 enzyme that is involved in the metabolic clearance of a wide variety of therapeutic agents, including nonsteroidal antiinflammatories, oral anticoagulants, and oral hypoglycemics. Disruption of CYP2C9 activity by metabolic inhibition or pharmacogenetic variability underlies many of the adverse drug reactions that are associated with the enzyme. CYP2C9 is also the first human P450 to be crystallized, and the structural basis for its substrate and inhibitor selectivity is becoming increasingly clear. New, ultrapotent inhibitors of CYP2C9 have been synthesised that aid in the development of quantitative structure-activity relationship (QSAR) models to facilitate drug redesign, and extensive resequencing of the gene and studies of its regulation will undoubtedly help us understand interindividual variability in drug response and toxicity controlled by this enzyme.
Rettie
Allan E
AE
Department of Medicinal Chemistry, University of Washington, Seattle, Washington 98195, USA. rettie@u.washington.edu
Jones
Jeffrey P
JP
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D065729:Cytochrome P-450 CYP2C9; D004347:Drug Interactions / Q000502:physiology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D010597:Pharmacogenetics / Q000379:methods*
D004791:Enzyme Inhibitors; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases