Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity.

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Bodin L, Verstuyft C, Tregouet DA, Robert A, Dubert L, Funck-Brentano C, Jaillon P, Beaune P, Laurent-Puig P, Becquemont L, Loriot MA

Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity.

Blood. 2005 Jul 1;106(1):135-40. Epub 2005 Mar 24.

PubMed ID

15790782 [ View in PubMed

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Abstract

The aim of the study is to explore the contribution of genetic factors related either to drug metabolism (cytochrome P450 2C9) or to drug target (vitamin K epoxide reductase) to variability in the response to acenocoumarol among 222 healthy volunteers after a single oral dose. Associations between a pharmacodynamic index (reduction in factor VII activity and international normalized ratio [INR] change) and several genetic polymorphisms (VKORC1: -4931T>C, -4451C>A, -2659G>C, -1877A>G, -1639G>A, 497C>G, 1173C>T, and CYP2C9*3) were investigated using haplotype and univariate analyses. VKORC1 haplotypes were associated with the pharmacologic response, and this association can be explained only by the effect of the -1639G>A polymorphism (or alternatively by 1173C>T, which is in complete association with it). Indeed, it explains about one third of the variability of the pharmacologic response (37% of factor VII decrease and 30% of INR change). Moreover, the previously observed effect of the CYP2C9*3 allele is independent of the VKORC1 gene effect. These 2 polymorphisms account for up to 50% of the interindividual variability. The simple genotyping of 2 single-nucleotide polymorphisms (SNPs), VKORC1 -1639G>A or 1173C>T and the CYP2C9*3 polymorphisms, could thus predict a high risk of overdose before initiation of anticoagulation with acenocoumarol, and provide a safer and more individualized anticoagulant therapy.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Acenocoumarol	Vitamin K epoxide reductase complex subunit 1	Protein	Humans	Yes	Inhibitor	Details