Clinical and toxicological relevance of CYP2C9: Drug-drug interactions and pharmacogenetics

• Published in: Annual review of pharmacology and toxicology 2005-01, Vol.45 (1), p.477-494
• Main Authors: RETTIE, Allan E, JONES, Jeffrey P
• Format: Article
• Language: English
• Subjects: Analytical, structural and metabolic biochemistry; Animals; Aryl Hydrocarbon Hydroxylases - antagonists & inhibitors; Aryl Hydrocarbon Hydroxylases - genetics; Aryl Hydrocarbon Hydroxylases - metabolism; Biological and medical sciences; Cytochrome P-450 CYP2C9; Drug Interactions - physiology; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Humans; Oxidoreductases; Pharmacogenetics - methods
• ISSN: 0362-1642; 1545-4304
• DOI: 10.1146/annurev.pharmtox.45.120403.095821

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.