Pharmacogenetics of acenocoumarol: CYP2C9, CYP2C19, CYP1A2, CYP3A4, CYP3A5 and ABCB1 gene polymorphisms and dose requirements.
Article Details
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Saraeva RB, Paskaleva ID, Doncheva E, Eap CB, Ganev VS
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.
- PubMed ID
- 18021343 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Acenocoumarol Cytochrome P450 1A2 Protein Humans UnknownSubstrateDetails Acenocoumarol Cytochrome P450 2C19 Protein Humans UnknownSubstrateDetails Acenocoumarol Cytochrome P450 2C9 Protein Humans UnknownSubstrateDetails - Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Acenocoumarol P-glycoprotein 1 Protein Humans UnknownSubstrateDetails - Pharmaco-genomics
Drug Interacting Gene/Enzyme Allele name Genotypes Defining change(s) Type(s) Description Details Acenocoumarol Cytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712CYP2C9*2 (T;T) / (C;T) - T Allele (rs1799853)
Effect Directly Studied The presence of this polymorphism in CYP2C9 is associated with reduction in acenocoumarol metabolism. Details Acenocoumarol Cytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712CYP2C9*3 (C;C) / (A;C) - C Allele (rs1057910)
Effect Directly Studied The presence of this polymorphism in CYP2C9 is associated with reduction in acenocoumarol metabolism. Details