Linder Mark W, Looney Stephen, Adams Jesse E, Johnson Nancy, Antonino-Green Deborah, Lacefield Nichole, Bukaveckas Bonny L, Valdes Roland
Department of Pathology and Laboratory Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA.
J Thromb Thrombolysis. 2002 Dec;14(3):227-32. doi: 10.1023/a:1025052827305.
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.
Patients stabilized on warfarin therapy were recruited from an anticoagulation clinic. Patients were genotyped for CYP2C92, CYP2C93 and CYP2C95 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 CYP2C95 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 CYP2C91/*1 genotype but did not influence dose requirement of subjects with one or more variant CYP2C9 alleles.
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 CYP2C92 and or CYP2C93 variant alleles. The variables of CYP2C9 genotype and age can be applied to restrict the dosage range considered for individual patients.
华法林的剂量反应关系不可预测。细胞色素P4502C9酶的多态性可能导致华法林超敏反应，这可能是由于S-对映体代谢减少所致。本研究的目的是进一步阐明CYP2C9基因型与表型之间的关系，并为解释CYP2C9基因型以指导华法林剂量调整制定指南提供依据。
从抗凝门诊招募接受华法林治疗且病情稳定的患者。采用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的CYP2C92、CYP2C93和CYP2C95等位基因进行基因分型。通过维持抗凝所需剂量（mg/kg/d）、（国际标准化比值2.0 - 3.0）、口服血浆S-华法林清除率以及血浆S:R-华法林比值来确定表型。在该队列中，未发现有受试者携带CYP2C95等位基因。血浆S-华法林浓度与年龄、剂量或CYP2C9基因型无关。CYP2C92和3等位基因均与较低的维持剂量、较低的总血浆和R-华法林浓度、S-华法林口服清除率降低、血浆S:R-华法林比值升高以及S-华法林消除半衰期延长有关。研究发现，年龄增长会使具有常见活性CYP2C9*1/*1基因型的受试者华法林维持剂量降低，但对具有一个或多个CYP2C9变异等位基因的受试者的剂量需求没有影响。
已滴定至一致目标国际标准化比值的受试者，其血浆S-华法林浓度与CYP2C9基因型无关。不同受试者维持一致目标国际标准化比值所需的华法林剂量因S-华法林清除率而异，而CYP2C92和/或CYP2C93变异等位基因均会降低S-华法林清除率。CYP2C9基因型和年龄变量可用于限制为个体患者考虑的剂量范围。
