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


CONCLUSIONS
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.


CONCLUSIONS
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.
Saraeva
R B
RB
Department of Chemistry and Biochemistry, Medical University of Sofia, Sofia, Bulgaria. r_saraeva@yahoo.com
Paskaleva
I D
ID
Doncheva
E
E
Eap
C B
CB
Ganev
V S
VS
D000074:Acenocoumarol / Q000008:administration & dosage*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics*; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic
D000925:Anticoagulants; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; C510164:CYP3A5 protein, human; D019388:Cytochrome P-450 CYP1A2; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000074:Acenocoumarol