[Vitamin K antagonists: from discovery to pharmacogenetics]

Vitamin K antagonists (VKA) are used for 60 years in the treatment and prevention of thromboembolic disease. VKA were first used as rodenticides. There was a growing use of VKA in humans after President Eisenhower received them after a heart attack in 1955. However, the use of VKA is still challenging because they are characterized by a narrow therapeutic index and a great inter-individual variability in the dose response to the drug. This variability can partly be explained by demographic, clinical and therapeutic factors, but also by genetic variations. 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 was identified as the pharmacological target of VKA. Genetic variations affecting both CYP2C9 and VKORC1 are associated with a significant decrease in the VKA dose requirements and an increased risk of bleeding. Genotyping both CYP2C9 and VKORC1 before the initiation of VKA allows to identify a subgroup of patients with an early response to VKA therapy, that expose them to overdosage and a higher bleeding risk. More recently, a polymorphism in the gene encoding CYP4F2 has been identified and may partly explain the variability in warfarin maintenance dose by altering the metabolism of vitamin K. In addition, rare mutations have been found in VKORC1 that could explain very high VKA dose requirements and pharmacodynamic resistance.