Becquemont Laurent
Pharmacology Department, Faculté de médecine Paris Sud, Université Paris-Sud, Le Kremlin Bicêtre, France.
Eur J Clin Pharmacol. 2008 Oct;64(10):953-60. doi: 10.1007/s00228-008-0542-2. Epub 2008 Aug 30.
Oral anticoagulants (OA) are a leading cause of fatal haemorrhagic adverse events in relation with an important interindividual variability of response to these drugs. Besides several clinical factors, this interindividual variability of response to OA has a pharmacogenetic basis. Carriers of cytochrome P450 2C9 (CYP2C9)-deficient alleles have a reduced clearance of warfarin and are exposed to dramatic overdoses in the first weeks of treatment. Genetic polymorphisms of vitamin K epoxide reductase (VKORC1), the target of OA, identify patients with a high sensitivity to OA who are at risk of early overdose. Most pharmacogenetic evidence is presently restricted to warfarin. Several warfarin dosing algorithms have been constructed, adapted on CYP2C9 and VKORC1 genotypes and clinical factors, to predict the best dose for each patient. Carriers of one of allelic variant need a 20-30% reduction of warfarin dose. However, definite evidence concerning the usefulness of these algorithms in terms of reducing the frequency of major bleeding episodes is still lacking. Ongoing prospective randomised trials will ascertain definitive answer over the coming years.
口服抗凝剂（OA）是导致致命性出血不良事件的主要原因，这些药物的个体反应存在重要差异。除了一些临床因素外，OA反应的个体差异具有药物遗传学基础。细胞色素P450 2C9（CYP2C9）缺陷等位基因的携带者华法林清除率降低，在治疗的最初几周会出现严重过量用药。OA的靶点维生素K环氧还原酶（VKORC1）的基因多态性可识别出对OA高度敏感、有早期过量用药风险的患者。目前，大多数药物遗传学证据仅限于华法林。已经构建了几种基于CYP2C9和VKORC1基因型及临床因素的华法林给药算法，以预测每位患者的最佳剂量。携带其中一种等位基因变异的患者需要将华法林剂量降低20% - 30%。然而，关于这些算法在降低大出血事件发生率方面的有效性，仍缺乏确凿证据。正在进行的前瞻性随机试验将在未来几年确定最终答案。
