OBJECTIVES:A broad range of phenytoin doses is used in clinical practice, with the final 'maintenance' dose normally determined by trial and error. A common functional polymorphism in the SCN1A gene (one of the genes encoding the drug target) has been previously associated with maximum dose of phenytoin used clinically, and also maximum dose of carbamazepine, another antiepileptic drug with the same drug target. METHODS:We have related variation at the SCN1A IVS5-91 G>A polymorphism to maximum dose and to maintenance dose of phenytoin in 168 patients with epilepsy treated with phenytoin. We also related genotype to phenytoin serum levels at maximum dose and at maintenance dose of phenytoin. We genotyped the polymorphism using an Applied Biosystems Taqman assay. RESULTS:The polymorphism is associated with phenytoin serum concentration at maintenance dose (P=0.03). In a reduced cohort of 71 patients receiving phenytoin monotherapy this association is also significant (P=0.03). Neither association remains significant after Bonferroni correction for multiple testing. CONCLUSIONS:These results are not a replication of the original study. They do, however, support the hypothesis that this polymorphism influences the clinical use of phenytoin. They also demonstrate the utility of using multiple phenotypes in pharmacogenetics studies, particularly when attempting to separate pharmacokinetic and pharmacodynamic effects. As the SCN1A polymorphism affects phenytoin pharmacodynamics, it is particularly useful to obtain data on serum levels in addition to dose because association of a pharmacodynamic variant may be stronger with serum levels than dose as the serum level may eliminate or reduce pharmacokinetic variability.

译文

目的:临床实践中广泛使用苯妥英钠剂量,最终的“维持”剂量通常由反复试验确定。 SCN1A基因(编码药物靶标的基因之一)中常见的功能多态性先前已与临床使用的苯妥英钠的最大剂量,以及具有相同药物靶点的另一种抗癫痫药卡马西平的最大剂量相关。
方法:在168例接受苯妥英治疗的癫痫患者中,SCN1A IVS5-91 G> A多态性与苯妥英的最大剂量和维持剂量相关。我们还将基因型与苯妥英最大剂量和维持剂量下的苯妥英血清水平相关。我们使用Applied Biosystems Taqman分析对基因多态性进行基因分型。
结果:多态性与维持剂量时苯妥英钠的血清浓度有关(P = 0.03)。在减少的接受苯妥英单药治疗的71名患者中,这一关联也很显着(P = 0.03)。在进行Bonferroni校正以进行多次测试后,这两个关联均不显着。
结论:这些结果不是原始研究的重复。但是,他们确实支持这种多态性影响苯妥英钠临床使用的假设。他们还证明了在药物遗传学研究中使用多种表型的效用,特别是在尝试分离药代动力学和药效学作用时。由于SCN1A多态性会影响苯妥英的药效学,因此获得除剂量外的血清水平数据特别有用,因为药理学变异与血药水平的关联可能比剂量更强,因为血清水平可能会消除或降低药代动力学的变异性。

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