CYP2C9和CYP2C19基因多态性对华法林维持剂量及代谢清除率的影响

Influence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance.

作者信息

Scordo Maria Gabriella, Pengo Vittorio, Spina Edoardo, Dahl Marja Liisa, Gusella Milena, Padrini Roberto

机构信息

Section of Pharmacology, Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Italy.

出版信息

Clin Pharmacol Ther. 2002 Dec;72(6):702-10. doi: 10.1067/mcp.2002.129321.

DOI:10.1067/mcp.2002.129321

PMID:12496751

Abstract

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 (<26.25 mg/wk; n = 37), medium (26.25-43.75 mg/wk; n = 32), and high (>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 (CL(free)) 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 CL(free) values were 307.5 mL/min, 480.3 mL/min, and 881.3 mL/min. The mean S-warfarin CL(free) values varied significantly among the CYP2C9 genotype groups (P <.0001), although most patients (72%) with no mutated alleles showed S-warfarin CL(free) values in the same range as those carrying mutated alleles (58-777 mL/min). No relationship was found between S-warfarin CL(free) and CYP2C19 genotype or between R-warfarin CL(free) and either CYP2C9 or CYP2C19 genotype.

CONCLUSION

CYP2C9 genetic polymorphisms markedly influence warfarin dose requirements and metabolic clearance of the S-warfarin enantiomer, although nongenetic factors may also contribute to their large interindividual variability.

摘要

目的

我们的目的是确定细胞色素P450（CYP）2C9和CYP2C19基因多态性对华法林剂量需求和代谢清除率的影响。

方法

研究人群包括93名接受长期华法林抗凝治疗（国际标准化比值，2 - 3）的意大利门诊患者，分为3个剂量组：低剂量组（<26.25 mg/周；n = 37）、中剂量组（26.25 - 43.75 mg/周；n = 32）和高剂量组（>43.75 mg/周；n = 24）。通过高效液相色谱法和平衡透析法测量S - 华法林和R - 华法林的稳态非结合血浆浓度，并计算相应的非结合口服清除率（CL(free)）值。通过聚合酶链反应，随后进行限制性酶切分析，鉴定CYP2C9（CYP2C9()2和CYP2C9()3）和CYP2C19（CYP2C19(*)2）的等位基因变体。

结果

54例患者未携带CYP2C9突变等位基因（()1/()1），31例携带一个（()1/()2，n = 15；()1/()3，n = 16），8例携带两个（()2/()2，n = 2；()3/()3，n = 2；()2/()3，n = 4）。2例受试者为CYP2C19(*)2等位基因变体的纯合子，19例为杂合子。低剂量组中CYP2C9突变等位基因的频率为72%，中剂量组为36%，高剂量组为4%；相应的平均S - 华法林CL(free)值分别为307.5 mL/分钟、480.3 mL/分钟和881.3 mL/分钟。CYP2C9基因型组之间的平均S - 华法林CL(free)值差异显著（P <.0001），尽管大多数未携带突变等位基因的患者（72%）的S - 华法林CL(free)值与携带突变等位基因的患者（58 - 777 mL/分钟）处于相同范围。未发现S - 华法林CL(free)与CYP2C19基因型之间或R - 华法林CL(free)与CYP2C9或CYP2C19基因型之间存在相关性。