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

@article{Bodin2005CytochromeP2,
  title={Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity.},
  author={Laurent Bodin and C{\'e}line Verstuyft and David Alexandre Tregouet and Annie Robert and Liliane Dubert and Christian Funck-Brentano and Patrice Jaillon and Philippe H. Beaune and Pierre Laurent-Puig and Laurent Becquemont and Marie-Anne Loriot},
  journal={Blood},
  year={2005},
  volume={106 1},
  pages={
          135-40
        }
}
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… 

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References

SHOWING 1-10 OF 31 REFERENCES
Association of pharmacokinetic (CYP2C9) and pharmacodynamic (factors II, VII, IX, and X; proteins S and C; and gamma-glutamyl carboxylase) gene variants with warfarin sensitivity.
TLDR
The results suggest that part of the considerable interpatient variation is attributable to genetic variation, and the combined genotyping of CYP2C9 and certain vitamin K-dependent protein genes is useful for predicting anticoagulant responses.
Pharmacogenetics of acenocoumarol: cytochrome P450 CYP2C9 polymorphisms influence dose requirements and stability of anticoagulation.
TLDR
CYP2C9*3 is related to lower acenocoumarol dose requirements, a higher frequency of over-anticoagulation at the initiation of therapy and an unstable anticoagulant response.
Cytochrome P4502C9 is the principal catalyst of racemic acenocoumarol hydroxylation reactions in human liver microsomes.
TLDR
It is demonstrated that (S)-acenocoumarol is hydroxylated by a single enzyme, namely CYP2C9, which is also the main enzyme in the 7-hydroxylation of (R)-acenticoagulant therapy.
Pharmacogenetics of oral anticoagulants.
TLDR
There is wide interindividual variation in oral anticoagulant dose requirement, which is partly genetically determined and may be due to unusually high CYP2C9 activity (pharmacokinetic resistance) or to an abnormality in the target enzyme vitamin K epoxide reductase (Pharmacodynamic resistance).
A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin.
TLDR
Genetic variants of the VKORC1 gene locus modulate the mean daily dose of drug prescribed to acquire the target anticoagulation intensity and accounted for about a third of the interindividual variability in the present setting.
Genetic analysis of the human cytochrome P450 CYP2C9 locus.
TLDR
Polymerase chain reaction-based assays are developed to distinguish all seven CYP2C9 cDNA sequences, and have determined their allele frequencies in the Caucasian population, allowing the prediction of CYP 2C9 phenotype, thus identifying those individuals who may exhibit different drug pharmacokinetics for CYP1C9 substrates.
The risk of bleeding complications in patients with cytochrome P450 CYP2C9*2 or CYP2C9*3 alleles on acenocoumarol or phenprocoumon.
TLDR
Having a variant allele of CYP2C9 was associated with an increased risk of major bleeding events in outpatients of an anticoagulation clinic using acenocoumarol or phen Procoumon, but not in patients on phenprocoumon.
Differential effects of 2C9*3 and 2C9*2 variants of cytochrome P-450 CYP2C9 on sensitivity to acenocoumarol.
TLDR
Because acenocoumarol sensitivity with the 2C9*2 variant does not seem to be clinically relevant, the drug could be an alternative to warfarin in 2C 9*2 carriers.
Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2
TLDR
The gene vitamin K epoxide reductase complex subunit 1 (VKORC1), which encodes a small transmembrane protein of the endoplasmic reticulum, is identified, by using linkage information from three species, to be involved in two heritable human diseases.
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