Genetic association between sensitivity to warfarin and expression of CYP2C9*3

Pharmacogenetics. 1997 Oct;7(5):361-7. doi: 10.1097/00008571-199710000-00004.


Cytochrome P4502C9 (CYP2C9) is largely responsible for terminating the anticoagulant effect of racemic warfarin via hydroxylation of the pharmacologically more potent S-enantiomer to inactive metabolites. Mutations in the CYP2C9 gene result in the expression of three allelic variants, CYP2C9*1, CYP2C9*2 and CYP2C9*3. Both CYP2C9*2 and CYP2C9*3 exhibit altered catalytic properties in vitro relative to the wild-type enzyme. In the present study, a patient was genotyped who had proven unusually sensitive to warfarin therapy and could tolerate no more than 0.5 mg of the racemic drug/day. PCR-amplification of exons 3 and 7 of the CYP2C9 gene, followed by restriction digest or sequence analysis, showed that this individual was homozygous for CYP2C9*3. In addition, patient plasma warfarin enantiomer ratios and urinary 7-hydroxywarfarin enantiomer ratios were determined by chiral-phase high performance liquid chromotography in order to investigate whether either parameter might be of diagnostic value in place of a genotypic test. Control patients receiving 4-8 mg warfarin/day exhibited plasma S:R ratios of 0.50 +/- 0.25:1, whereas the patient on very low-dose warfarin exhibited an S:R ratio of 3.9:1. In contrast, the urinary 7-hydroxywarfarin S:R ratio of 4:1 showed the same stereoselectivity as that reported for control patients. Therefore, expression of CYP2C9*3 is associated with diminished clearance of S-warfarin and a dangerously exacerbated therapeutic response to normal doses of the racemic drug. Analysis of the plasma S:R warfarin ratio may serve as a useful alternative test to genotyping for this genetic defect.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Anticoagulants / pharmacokinetics
  • Anticoagulants / pharmacology*
  • Aryl Hydrocarbon Hydroxylases*
  • Cytochrome P-450 CYP2C9
  • Cytochrome P-450 Enzyme System / genetics*
  • Cytochrome P-450 Enzyme System / metabolism
  • Heterozygote
  • Homozygote
  • Humans
  • Male
  • Middle Aged
  • Phenotype
  • Stereoisomerism
  • Steroid 16-alpha-Hydroxylase*
  • Steroid Hydroxylases / genetics*
  • Steroid Hydroxylases / metabolism
  • Warfarin / pharmacokinetics
  • Warfarin / pharmacology*


  • Anticoagulants
  • Warfarin
  • Cytochrome P-450 Enzyme System
  • Steroid Hydroxylases
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Aryl Hydrocarbon Hydroxylases
  • Steroid 16-alpha-Hydroxylase