RESUMO
Alterations in vitamin K availability can significantly influence anticoagulation response to warfarin. Apolipoprotein E (APOE) plays a part in the hepatic uptake of lipid-soluble vitamin K. This study aimed to determine the influence of common polymorphisms in the APOE gene on warfarin dose requirements. patients with stable anticoagulation control and with a target International Normalized Ratio (INR) 2.0-3.0 were genotyped for the APOE epsilon2, epsilon3 and epsilon4 variants. Mean +/- SD daily warfarin doses were significantly lower in patients carrying at least one epsilon4 allele compared to the epsilon3epsilon3 reference genotype (3.3 +/- 1.9 versus 4.0 +/- 1.8; P = 0.03; 95% CI: 0.1-1.2). Multivariate regression analysis showed that patient age, height and CYP2C9, VKORC1 and APOE genotypes significantly contributed to warfarin dose requirement (R = 57%). only the epsilon4 allele of APOE was found to make a significant (P = 0.002) but small contribution to warfarin dose requirement. There was no significant difference in fasted plasma vitamin K concentration between patients with the different APOE genotypes. This study suggests that APOE genotype is unlikely to have a clinically significant effect on warfarin dose requirements.
Assuntos
Apolipoproteínas E/genética , Deficiência de Vitamina K/tratamento farmacológico , Varfarina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/uso terapêutico , Apolipoproteínas E/fisiologia , Transtornos da Coagulação Sanguínea/tratamento farmacológico , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético/fisiologia , Deficiência de Vitamina K/genética , Varfarina/administração & dosagemRESUMO
Current dosing algorithms do not account for genetic and environmental factors for warfarin dose determinations. This study investigated the contribution of age, CYP2C9 and VKORC1 genotype, and body size to warfarin-dose requirements. Studied were 297 patients with stable anticoagulation with a target international normalized ratio (INR) of 2.0 to 3.0. Genetic analyses for CYP2C9 (*2 and *3 alleles) and VKORC1 (-1639 polymorphism) were performed and venous INR and plasma R- and S-warfarin concentrations determined. The mean warfarin daily dose requirement was highest in CYP2C9 homozygous wild-type patients, compared with those with the variant *2 and *3 alleles (P < .001) and highest in patients with the VKORC1 (position -1639) GG genotype compared with those with the GA genotype and the AA genotype (P < .001). Mean warfarin daily dose requirements fell by 0.5 to 0.7 mg per decade between the ages of 20 to 90 years. Age, height, and CYP2C9 genotype significantly contributed to S-warfarin and total warfarin clearance, whereas only age and body size significantly contributed to R-warfarin clearance. The multivariate regression model including the variables of age, CYP2C9 and VKORC1 genotype, and height produced the best model for estimating warfarin dose (R2 = 55%). Based upon the data, a new warfarin dosing regimen has been developed. The validity of the dosing regimen was confirmed in a second cohort of patients on warfarin therapy.
Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Oxigenases de Função Mista/genética , Farmacogenética/métodos , Polimorfismo Genético , Varfarina/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Alelos , Anticoagulantes/administração & dosagem , Estudos de Coortes , Citocromo P-450 CYP2C9 , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Genótipo , Homozigoto , Humanos , Coeficiente Internacional Normatizado , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Análise de Regressão , Vitamina K Epóxido RedutasesAssuntos
Doenças Cardiovasculares/tratamento farmacológico , Hiperlipidemias/tratamento farmacológico , Osteoporose/tratamento farmacológico , Padrões de Prática Médica , Antagonistas Adrenérgicos beta/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Aspirina/uso terapêutico , Humanos , Hipertensão/tratamento farmacológico , Infarto do Miocárdio/tratamento farmacológico , Educação de Pacientes como Assunto/métodos , Terapia TrombolíticaRESUMO
BACKGROUND: avoidance of over anticoagulation in response to warfarin therapy would reduce risk of associated bleeding. SUBJECTS: two elderly patients with venous thromboembolism exhibited extreme anticoagulant response to warfarin. Both were noted to have variant CYP2C9 alleles, which reduce the metabolic capacity of cytochrome P450 2C9. DISCUSSION: adverse outcomes with warfarin therapy could be explained and possibly avoided by identifying patients with variant alleles for CYP2C9 before initiation of therapy.