ABSTRACT
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.
Subject(s)
Anticoagulants/therapeutic use , Aryl Hydrocarbon Hydroxylases/genetics , Blood Coagulation/genetics , DNA/genetics , Polymorphism, Genetic , Thrombosis/genetics , Warfarin/therapeutic use , Anticoagulants/pharmacokinetics , Blood Coagulation/drug effects , Cytochrome P-450 CYP2C9 , Female , Follow-Up Studies , Hemorrhage/blood , Hemorrhage/chemically induced , Hemorrhage/genetics , Humans , Male , Middle Aged , Polymerase Chain Reaction , Risk Factors , Thrombosis/blood , Thrombosis/drug therapy , Time Factors , Treatment Outcome , Warfarin/administration & dosage , Warfarin/pharmacokineticsABSTRACT
CYP2C9 is the main enzyme participating in warfarin metabolism, of which genetic polymorphism is typical. The aim of the study was to investigate the influence of having allelic variants CYP2C9*2 and CYP2C9*3 on the pharmacokinetics, dosage regimen, and the rate of hemorrhage in patients with constant atrial fibrillation taking warfarin. Eighty-two patients with constant atrial fibrillation taking warfarin were included in the study. It was shown that in patients with CYP2C9*2 and CYP2C9*3 the clearance of warfarin and its dose were lower, while the episodes of excessive hypocoagulation and hemorrhage associated with warfarin were more frequent than in patients without these allelic variants. Basing on the results of the study, the authors propose an algorithm of choosing the initial warfarin dose depending on CYP2C9 genotype.
Subject(s)
Anticoagulants/pharmacokinetics , Aryl Hydrocarbon Hydroxylases/genetics , Atrial Fibrillation , DNA/genetics , Polymorphism, Genetic , Warfarin/pharmacokinetics , Alleles , Anticoagulants/administration & dosage , Anticoagulants/adverse effects , Atrial Fibrillation/blood , Atrial Fibrillation/drug therapy , Atrial Fibrillation/genetics , Cytochrome P-450 CYP2C9 , Dose-Response Relationship, Drug , Female , Follow-Up Studies , Hemorrhage/chemically induced , Hemorrhage/epidemiology , Hemorrhage/genetics , Humans , Incidence , Male , Middle Aged , Polymerase Chain Reaction , Prognosis , Risk Factors , Thrombophilia/chemically induced , Thrombophilia/epidemiology , Thrombophilia/genetics , Warfarin/administration & dosage , Warfarin/adverse effectsABSTRACT
The review is devoted to the contemporary state of the problem of pharmacogenetics of indirect anticoagulants. At present there are data about effects of allele variants of CYP2C9, VKORC1, APOE genes on efficacy and safety of therapy with indirect anticoagulants. Detection of these variants is a perspective way to individualization of therapy with indirect anticoagulants.
