Warfarin dose adjustments based on CYP2C9 genetic polymorphisms
Warfarin dose adjustments based on CYP2C9 genetic polymorphisms
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DOI：
10.1023/a:1025052827305
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发表时间：
2002-12-01
影响因子：
4
通讯作者：
Valdes, R
中科院分区：
文献类型：
--
作者：
Linder, MW;Looney, S;Valdes, R
背景：华法林的剂量反应关系是不可预测的。细胞色素P4502 C9酶的多态性导致华法林超敏反应，可能是由于S-对映体代谢降低所致。本研究的目的是进一步描述CYP 2C 9基因型和表型之间的关系，并制定一个指导方针的基础上解释CYP 2C 9基因型华法林dosing.Methods和结果：华法林治疗稳定的患者从抗凝临床招募。通过聚合酶链反应扩增和限制性内切酶消化的标准方法对患者进行CYP 2C 9 *2、CYP 2C 9 *3和CYP 2C 9 *5等位基因的基因分型。表型确定为：维持抗凝所需的剂量（mg/kg/d）、（INR 2.0-3.0）、口服血浆S-华法林清除率和血浆S：R-华法林比值。在该队列中，未发现受试者具有CYP 2C 9 *5等位基因。血浆S-华法林浓度不随年龄、剂量或CYP 2C 9基因型而变化。CYP 2C 9 *2和 *3等位基因均与维持剂量较低、总华法林和R-华法林血浆浓度较低、S-华法林口服清除率降低、血浆S：R-华法林比值升高和S-华法林消除半衰期延长相关。研究发现，年龄的增加会降低常见的活性CYP 2C 9 *1/*1基因型受试者的华法林维持剂量，但不会影响一个或多个变异CYP 2C 9等位基因的受试者的剂量要求。结论：受试者已滴定至一致的目标INR，表明血浆S-华法林浓度与CYP 2C 9基因型无关。受试者之间维持一致目标INR所需的华法林剂量因S-华法林清除率而异，S-华法林清除率因CYP 2C 9 *2和/或CYP 2C 9 *3变异等位基因而降低。CYP 2C 9基因型和年龄变量可用于限制个体患者考虑的剂量范围。
Background: The dose response relationship of warfarin is unpredictable. Polymorphism of the Cytochrome P4502C9 enzyme leads to warfarin hypersensitivity presumably due to decreased metabolism of the S-enantiomer. The purpose of this study was to further characterize the relationship between CYP2C9 genotype and phenotype and to develop a basis for guidelines to interpret CYP2C9 genotype for warfarin dosing.Methods and results: Patients stabilized on warfarin therapy were recruited from an anticoagulation clinic. Patients were genotyped for CYP2C9*2, CYP2C9*3 and CYP2C9*5 alleles by standard methods of polymerase chain reaction amplification and restriction endonuclease digestion. Phenotype was determined by; dose (mg/kg/d) required to maintain anticoagulation, (INR 2.0-3.0), oral plasma S-warfarin clearance, and the plasma S:R-warfarin ratio. In this cohort, no subjects were found to have the CYP2C9*5 allele. The plasma S-warfarin concentration did not differ with age, dose or CYP2C9 genotype. Both CYP2C9*2 and *3 alleles were associated with lower maintenance dosages, lower total and R-warfarin plasma concentrations, decreased oral clearance of S-warfarin, increased plasma S:R-warfarin ratio and extended S-warfarin elimination half-life. Advancing age was found to decrease Warfarin maintenance dose in subjects with the common active CYP2C9*1/*1 genotype but did not influence dose requirement of subjects with one or more variant CYP2C9 alleles.Conclusions: Subjects who have been titrated to a consistent target INR demonstrate comparable plasma S-warfarin concentrations independent of CYP2C9 genotype. The warfarin dose required to maintain a consistent target INR between subjects differs as a function of S-warfarin clearance which is decreased by both CYP2C9*2 and or CYP2C9*3 variant alleles. The variables of CYP2C9 genotype and age can be applied to restrict the dosage range considered for individual patients.