[The pharmacogenetics of vitamin K antagonists: still a matter for discussion].
The use of vitamin K antagonists (VKA) is challenging because of their narrow therapeutic index and a high bleeding risk. These drugs are widely prescribed for the prophylaxis and treatment of many thrombo-embolic disorders. The management of patients with VKA represents a public health problem according to the high number of deaths and hospitalizations in relation to hemorrhagic complications. Monitoring is required because of the large inter-individual variability. The identification of factors, in particular genetic factors, influencing the response to VKA will improve the safety of VKA treatment. In addition to demographic, clinical, biological factors and drug interactions, genetic factors can explain a large part of the inter-individual variability. The main enzyme responsible for VKA metabolism is the hepatic cytochrome P450 2C9 (CYP2C9). Vitamin K epoxide reductase complex subunit I (VKORC1) is a key enzyme in the vitamin K cycle and is the pharmacological target of VKA. Genetic variations affecting both CYP2C9 and VKORC1 are associated with a significant decrease in the VKA dose requirement and an increased risk of bleeding. CYP2C9 and VKORC1 genotyping may identify a subgroup of patients with an early response at the induction of VKA therapy, potentially leading to a high bleeding risk. On the opposite, rare mutations in VKORC1 can explain high dose requirement and pharmacodynamic resistance. Genotyping CYP2C9 and VKORC1 variants before treatment initiation could allow the development of dosing protocols and the identification of patients at high risk of bleeding complications.
Moreau
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C
Inserm UMRS775 Bases moléculaires de réponse aux xénobiotiques, 45, rue des Saints-Pères, université Paris Descartes, 75270 Paris cedex 06, France.
Siguret
V
V
Loriot
M-A
MA
D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D005838:Genotype; D006470:Hemorrhage / Q000139:chemically induced / Q000235:genetics; D006801:Humans; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009154:Mutation; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D013923:Thromboembolism / Q000150:complications / Q000188:drug therapy; D014812:Vitamin K / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D064417:Vitamin K Epoxide Reductases
D014812:Vitamin K; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases