Institute of Cellular Medicine, Newcastle University Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
Arch Toxicol. 2013 Mar;87(3):407-20. doi: 10.1007/s00204-013-1013-9. Epub 2013 Feb 2.
Coumarin anticoagulants, which include warfarin, acenocoumarol and phenprocoumon, are among the most widely prescribed drugs worldwide. There is now a large body of published data showing that genotype for certain common polymorphisms in the genes encoding the target vitamin K epoxide reductase (G-1639A/C1173T) and the main metabolizing enzyme CYP2C9 (CYP2C9*2 and *3 alleles) are important determinants of the individual coumarin anticoagulant dose requirement. Additional less common polymorphisms in these genes together with polymorphisms in other genes relevant to blood coagulation such as the cytochrome P450 CYP4F2, gamma-glutamyl carboxylase, calumenin and cytochrome P450 oxidoreductase may also be significant predictors of dose, especially in ethnic groups such as Africans where there have been fewer genetic studies compared with European populations. Using relevant genotypes to calculate starting dose may improve safety during the initiation period. Various algorithms for dose calculation, which also take patient age and other characteristics into consideration, have been developed for all three widely used coumarin anticoagulants and are now being tested in ongoing large randomised clinical trials. One recently completed study has provided encouraging results suggesting that calculation of warfarin dose on the basis of individual patient genotype leads to few adverse events and a higher proportion of time within the therapeutic coagulation rate window, but these findings still need confirmation.
香豆素类抗凝剂，包括华法林、醋硝香豆素和苯丙香豆素，是全球应用最广泛的药物之一。目前有大量的已发表数据表明，编码维生素 K 环氧化物还原酶（G-1639A/C1173T）和主要代谢酶 CYP2C9（CYP2C9*2 和 *3 等位基因）的某些常见基因多态性的基因型是个体香豆素类抗凝剂剂量需求的重要决定因素。这些基因中的其他较少见的多态性以及与凝血相关的其他基因中的多态性，如细胞色素 P450 CYP4F2、γ-谷氨酰羧化酶、钙网蛋白和细胞色素 P450 氧化还原酶，也可能是剂量的重要预测因子，尤其是在非洲等种族群体中，与欧洲人群相比，遗传研究较少。使用相关基因型计算起始剂量可能会提高起始阶段的安全性。目前已经针对三种广泛使用的香豆素类抗凝剂开发了各种剂量计算算法，这些算法还考虑了患者年龄和其他特征，并且正在正在进行的大型随机临床试验中进行测试。最近完成的一项研究提供了令人鼓舞的结果，表明根据个体患者基因型计算华法林剂量可导致较少的不良事件和治疗性凝血速率范围内的时间比例更高，但这些发现仍需确认。
