Kamali Farhad
School of Clinical and Laboratory Sciences, Wolfson Unit of Clinical Pharmacology, Claremont Place, University of Newcastle, Newcastle upon Tyne, UK.
Curr Opin Hematol. 2006 Sep;13(5):357-61. doi: 10.1097/01.moh.0000239708.70792.4f.
Warfarin has a narrow therapeutic index and there is wide interindividual variability in the drug dose requirement. Uncertainty of response renders currently used loading regimens inaccurate as they fail to take into account individual patient factors that have a major influence on anticoagulation response. This review focuses on recent research findings demonstrating the impact of genetics on warfarin sensitivity and dose requirement and the issues concerning the clinical utility of individualized therapy.
Single-nucleotide polymorphisms in cytochrome P450 2C9 and vitamin K epoxide reductase have been shown to make significant contributions to the variability in warfarin dose requirements. Polymorphisms in other genes that mediate the actions of warfarin make little or no contribution to the variability. Racial and cultural differences influence dose requirements, which can be explained at least in part by genetic and dietary factors.
Individualization of therapy based on genetic and environmental factors has the potential to reduce the adverse effects associated with the commencement of warfarin therapy. Prospective studies that incorporate both CYP2C9 and VKORC1 genes and environmental factors in warfarin dose calculation will be required to demonstrate the safety, cost-effectiveness, and feasibility of individualized dosing regimens.
华法林的治疗指数较窄，药物剂量需求存在较大的个体差异。由于目前使用的负荷方案未能考虑到对抗凝反应有重大影响的个体患者因素，因此反应的不确定性使得这些方案不准确。本综述重点关注近期的研究结果，这些结果表明基因对华法林敏感性和剂量需求的影响以及个体化治疗临床应用方面的问题。
细胞色素P450 2C9和维生素K环氧化物还原酶中的单核苷酸多态性已被证明对华法林剂量需求的变异性有重大影响。其他介导华法林作用的基因中的多态性对变异性影响很小或没有影响。种族和文化差异会影响剂量需求，这至少可以部分地由遗传和饮食因素来解释。
基于遗传和环境因素的个体化治疗有可能减少与华法林治疗开始相关的不良反应。需要进行前瞻性研究，将CYP2C9和VKORC1基因以及环境因素纳入华法林剂量计算，以证明个体化给药方案的安全性、成本效益和可行性。
