Pharmacogenetics of acenocoumarol: CYP2C9, CYP2C19, CYP1A2, CYP3A4, CYP3A5 and ABCB1 gene polymorphisms and dose requirements

J Clin Pharm Ther. 2007 Dec;32(6):641-9. doi: 10.1111/j.1365-2710.2007.00870.x.


Background and objective: Acenocoumarol (AC) is a coumarin derivative, vitamin K antagonist anticoagulant drug. It has a narrow therapeutic index and shows large pharmacokinetic and pharmacodynamic interindividual variability. Our objective was to investigate the association between AC dose requirements to achieve a target level of anticoagulation and genetic polymorphisms of genes possibly associated with its metabolism (CYP1A2, CYP2C9, CYP2C19, CYP3A4, CYP3A5) and transport (ABCB1).

Methods: Ninety-six Bulgarian patients treated orally with AC for at least 3 months were included. They were separated into three groups according to their AC dose requirement, i.e. low, medium and high.

Results and discussion: CYP2C9*1/*3 (associated with an intermediate CYP2C9 activity), CYP2C9*2/*2, and CYP2C9*2/*3 genotypes (associated with a low CYP2C9 activity) were more prevalent in the group with low dose requirement of AC compared with the other two groups (P = 0.003). The frequency of CYP2C9*1/*1 genotype, which is associated with an extensive CYP2C9 activity, was higher in the group of patients with high dose requirements (79%), compared with the groups of the medium and low dose requirements (67% and 21% respectively). In addition, the ABCB1 2677GG/3435CC haplotype was associated with use of lower AC dose, whereas the 2677TT/3435TT and 2677GT/3435TT haplotypes were associated with use of higher AC dose (P = 0.03). The distribution of polymorphisms of other genes did not show significant differences between the three groups.

Conclusion: In vivo, cytochromes P450 isoforms other than CYP2C9 [DOSAGE ERROR CORRECTED] were not significantly associated with dose requirement of AC. In our Bulgarian patients, the presence of CYP2C9*2 or/and CYP2C9*3 alleles, as well as the ABCB1 2677GG/3435CC haplotype were associated with low dose requirement of AC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acenocoumarol / administration & dosage*
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Anticoagulants / administration & dosage*
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Cytochrome P-450 CYP1A2 / genetics*
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 CYP2C9
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / genetics*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Mixed Function Oxygenases / genetics*
  • Pharmacogenetics
  • Polymorphism, Genetic


  • Anticoagulants
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C19 protein, human
  • CYP3A5 protein, human
  • Cytochrome P-450 CYP1A2
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Acenocoumarol