Influence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance
Influence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance
复制标题
DOI：
10.1067/mcp.2002.129321
复制
发表时间：
2002-12-01
影响因子：
6.7
通讯作者：
Padrini, R
中科院分区：
文献类型：
--
作者：
Scordo, MG;Pengo, V;Padrini, R
目的：探讨细胞色素P450(CYP)2C9和细胞色素P2C19基因多态性对华法林剂量需求和代谢清晰度的影响。方法：93例接受华法林长期抗凝治疗的意大利门诊患者分为3个剂量组：低剂量组(43.75 mg/wk；n=24)。用高效液相色谱法和平衡透析法测定S和R-华法林的稳态血药浓度，并计算相应的无结合口腔清除量(CLFree)。结果：54例患者未检出突变等位基因(*1/*1)，31例携带一种突变等位基因(*1/*2，n=15；*1/*3，n=16)，8例携带两种突变等位基因(*2/*2，n=2；*3/*3，n=4)。2名受试者为纯合子，19名为杂合子。低剂量组、中剂量组、高剂量组突变等位基因频率分别为72%、36%、4%，相应的S-华法林CLFF值平均值分别为307.5、480.3、881.3毫升/分。不同基因型组间的S-华法林CLFRE值差异有统计学意义(P
Objective: Our objective was to determine the influence of cytochrome P450 (CYP) 2C9 and CYP2C19 genetic polymorphisms on warfarin dose requirement and metabolic clearance.Methods: The study population consisted of 93 Italian outpatients receiving long-term warfarin anticoagulant therapy (international normalized ratio values, 2-3), divided into 3 dose groups: low (43.75 mg/wk; n=24). Steady-state unbound plasma concentrations of S- and R-warfarin were measured by HPLC and equilibrium dialysis, and corresponding unbound oral clearance (CLfree) values were calculated. Allelic variants of CYP2C9 (CYP2C9*2 and CYP2C9*3) and CYP2C19 (CYP2C19*2) were identified by polymerase chain reaction, followed by restriction enzyme analysis.Results: Fifty-four patients carried no CYP2C9 mutated alleles (*1/*1), 31 carried one (*1/*2, n=15; and *1/*3, n=16), and 8 carried two (*2/*2, n=2; *3/*3, n=2; and *2/*3, n=4). Two subjects were homozygous and 19 were heterozygous for the CYP2C19*2 allele variant. The frequencies of CYP2C9 mutated alleles were 72% in the low-dose group, 36% in the medium-dose group, and 4% in the high-dose group; the corresponding mean S-warfarin CLfree values were 307.5 mL/min, 480.3 mL/min, and 881.3 mL/min. The mean S-warfarin CLfree values varied significantly among the CYP2C9 genotype groups (P