Pharmacogenetics of acenocoumarol: cytochrome P450 CYP2C9 polymorphisms influence dose requirements and stability of anticoagulation.
OBJECTIVE
Cytochrome P4502C9 (CYP2C9) is the main enzyme implicated in coumarinic metabolism. Variant alleles, CYP2C9*2 and CYP2C9*3, have been related to decreased enzymatic activity, but their clinical relevance in acenocoumarol metabolism has not been established. We investigated CYP2C9 polymorphisms in relation to acenocoumarol dose requirement, stability of anticoagulation and bleeding.


METHODS
CYP2C9 genotyping was performed in 325 acenocoumarol-treated patients (INR target between 2.0 and 3.0) and in an additional group of 84 patients with repeated bleeding.


RESULTS
Patients with the wild-type CYP2C9*1/*1 genotype (n=169) required a higher maintenance dose of acenocoumarol (17.1 8.7 mg/week) than did patients with the CYP2C9*2 (14.6 6.4 mg/week, p<0.05, N=97) or the CYP2C9*3 allele (11.2 6.2 mg/week, p<0.001, n=59). Out of 170 patients requiring a low-dose of acenocoumarol (<or= 2 mg/day), 27.1% carried the CYP2C9*3 allele, while among the patients requiring higher doses, 8.4% had CYP2C9*3 (OR=4.77, 95% CI = 2.40-9.48, p<0.001 vs. 2C9*1/*1 patients). In the multivariate analysis, independent predictive variables for low-dose acenocoumarol requirements were age >70 years (OR=3.73, 95%CI=2.29-6.08, p<0.001), and the CYP2C9*3 allele (OR=4.75, 95%CI=2.36-9.55, p <0.001). Carriers of CYP2C9*3 spent less time within the therapeutic range (64.7 23.1%) than did patients with the CYP2C9*1/*1 genotype (75.1 22.0%, p<0.01), and more frequently had an INR >4.5 at the initiation of treatment (43.9% vs.11.6%, p<0.001), but did not show repeated bleeding more frequently (19.0% vs.15.5%, p=NS).


CONCLUSIONS
CYP2C9*3 is related to lower acenocoumarol dose requirements, a higher frequency of over-anticoagulation at the initiation of therapy and an unstable anticoagulant response.
Tàssies
Dolors
D
Hemotherapy and Hemostasis Department, Hospital Clinic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. dtassies@clinic.ub.es
Freire
Carolina
C
Pijoan
Josefina
J
Maragall
Santiago
S
Monteagudo
Joan
J
Ordinas
Antoni
A
Reverter
Joan Carles
JC
D000074:Acenocoumarol / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001777:Blood Coagulation / Q000187:drug effects; D065729:Cytochrome P-450 CYP2C9; D004355:Drug Stability; D005260:Female; D005838:Genotype; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D012189:Retrospective Studies
D000925:Anticoagulants; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D000074:Acenocoumarol