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Pharmacogenetics of oral anticoagulants

Lookup NU author(s): Professor Ann Daly, Dr Barry King

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Abstract

There is wide interindividual variation in oral anticoagulant dose requirement, which is partly genetically determined. Several cytochrome P450s contribute to oxidative metabolism of oral anticoagulants. The most important of these is CYP2C9, which hydroxylates the S-enantiomers of warfarin, acenocoumarol and phenprocoumon with high catalytic activity. In at least eight separate clinical studies, possession of the CYP2C9*2 or CYP2C9*3 variant alleles, which result in decreased enzyme activity, has been associated with a significant decrease in a mean warfarin dose requirement. Several studies also suggest that possession of a CYP2C9 variant allele is associated with an increased risk of adverse events, such as bleeding. Possession of the CYP2C9*3 variant also appears to be associated with a low acenocoumarol dose requirement. Other genetic factors, such as polymorphisms in the cytochromes P450 that metabolize the R-enantiomers of warfarin and acenocoumarol, may also be relevant to anticoagulant dose. The molecular basis of anticoagulant resistance where a higher than normal dose of anticoagulant is required remains unclear, but could be due to unusually high CYP2C9 activity (pharmacokinetic resistance) or to an abnormality in the target enzyme vitamin K epoxide reductase (pharmacodynamic resistance). © 2003 Lippincott Williams & Wilkins.


Publication metadata

Author(s): Daly AK, King BP

Publication type: Note

Publication status: Published

Journal: Pharmacogenetics

Year: 2003

Volume: 13

Issue: 5

Pages: 247-252

Print publication date: 01/05/2003

ISSN (print): 0960-314X

ISSN (electronic): 1744-6880

URL: http://dx.doi.org/10.1097/00008571-200305000-00002

DOI: 10.1097/00008571-200305000-00002

PubMed id: 12724615


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