title: Contribution of CYP2C9 to variability in vitamin K antagonist metabolism.
abstract: CYP2C9 is the third most important cytochrome P450 (CYP) in terms of number of drugs metabolised. A considerable amount of information on this isoform is now available with respect to its structural biology, the mechanisms by which it can be induced and the existence of a range of variant alleles, which are often functionally significant. CYP2C9 makes a very important contribution to metabolism of vitamin K antagonist anticoagulants, and is the main oxidising enzyme for S-warfarin and S-acenocoumarol as well as contributing to phenprocoumon metabolism. A large number of studies have now shown that CYP2C9 genotype predicts dose requirement for both warfarin and acenocoumarol, with a possible contribution for phenprocoumon. Patients with variant alleles are likely to require a lower dose and may be at risk of overcoagulation and resultant bleeding, especially during the induction phase of therapy. Although CYP2C9 genotype is clearly a predictor of vitamin K antagonist dose requirement, especially in Caucasian populations in whom variant alleles are common, a number of recent studies have shown that age, genotype for the gene encoding the target gene vitamin K epoxide reductase and concomitant drugs are equally important factors in determining dose. There is a need for prospective studies to assess the value of predicting dose requirement on the basis of all these factors, including the CYP2C9 genotype.
authors.affiliation: University of Newcastle Medical School, School of Clinical and Laboratory Sciences, Framlington Place, Newcastle upon Tyne, UK. A.K.Daly@ncl.ac.uk
authors.forename: Ann K
authors.initials: AK
authors.lastname: Daly
authors.forename: Barry P
authors.initials: BP
authors.lastname: King
mesh_terms: D000483:Alleles; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000097:blood* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000097:blood / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D014644:Genetic Variation / Q000502:physiology*; D005838:Genotype; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics; D014812:Vitamin K / Q000037:antagonists & inhibitors* / Q000097:blood / Q000235:genetics; D064417:Vitamin K Epoxide Reductases
chemical_list: D000925:Anticoagulants; D007527:Isoenzymes; D014812:Vitamin K; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D064417:Vitamin K Epoxide Reductases