[Cytochrome P4502C9(CYP2C9) gene polymorphism and safety of therapy with warfarin].
Aim of the study was to investigate frequency and influence of alleles CYP2C9*2 and CYP2C9*3 on pharmacokinetics, pharmacodynamics and dosing regimen of warfarin and on development of hemorrhagic complications. We included 84 patients (mean age 62,8 +/- 10,5 years). Duration of follow-up varied between 1 month and 1 year. Carriage of allele variants was determined by polymerase chain reaction, measurement of plasma wafarin concentration was carried out with the help of high performance liquid chromatography. Wild type (CYP2C9*1/*1) was found in 68% of patients; overall frequency of 2C9*1/*1, *l/*3, *2/*2, *3/*3, *2/*3 genotypes was 32%. Average maintenance doses of warfarin for patients with allele variants CYP 2C9 *2 and 2C9 *3 were 3.6 and 3.1 mg/day, respectively, what was significantly lower than in wild type homozygotes (6.1 mg/day). Wild type homozygotes (1) had the highest warfarin clearance (3,51 ml/min). In carriers of 2C9 *2(2) and 2C9 *3(3) warfarin clearance was significantly lower (2.42 and 1.82 ml/min; p1 - 2 = 0,05; p1 - 3 = 0,0008). In carriers of allele variants CYP2C9*2, CYP2C9*3 values of international normalized ratio > 3,0 were met more often, especially in carriers of CYP2C9*3 (in 100% of cases) vs. 28% in wild type homozygotes (p=0,02). Carriers of CYP2C9*3 compared with wild type homozygotes had more hemorrhagic complications (67% and 16%, respectively, p=0,0008). Thus cytochrome P450 2C9 gene polymorphism influences frequency of development of hemorrhagic complications, metabolic clearance, and magnitude of warfarin maintenance dose.
Mikheeva
Iu A
IuA
Cardiology Research Complex, Moscow, Russia.
Kropacheva
E S
ES
Ignat'ev
I V
IV
Bulytova
Iu M
IuM
Ramenskaia
G V
GV
Sychev
D A
DA
Dobrovol'skiĭ
A B
AB
Panchenko
E P
EP
D000925:Anticoagulants / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001777:Blood Coagulation / Q000187:drug effects / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D004247:DNA / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006470:Hemorrhage / Q000097:blood / Q000139:chemically induced / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012307:Risk Factors; D013927:Thrombosis / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D013997:Time Factors; D016896:Treatment Outcome; D014859:Warfarin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000925:Anticoagulants; D014859:Warfarin; D004247:DNA; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases