Yamamoto Yoshiaki, Takahashi Yukitoshi, Nishimura Shigeko, Ikumi Yasuhiro, Mishima Nobuyuki, Kagawa Yoshiyuki
Department of Clinical Research, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan.
Yakugaku Zasshi. 2011;131(5):809-15. doi: 10.1248/yakushi.131.809.
Genetic polymorphism of cytochrome P450 2C9 (CYP2C9) and cytochrome P450 2C19 (CYP2C19) is widely known to contribute to interindividual differences in the pharmacokinetics of some antiepileptic drugs. We developed a rapid detection assay of polymorphisms of CYP2C9 and CYP2C19, using the Light Cycler(®) polymerase chain reaction (PCR) system. Using this assay, we examined polymorphisms in 20 Japanese pediatric patients prescribed phenytoin for the treatment of epilepsy, and classified their polymorphisms into four groups: group I, CYP2C9*1/1 and CYP2C191/1; group II, CYP2C91/1 and CYP2C191/*2 or *1/3; group III, CYP2C91/1 and CYP2C192/2; and group IV, CYP2C91/3 and CYP2C191/*2 or *1/*3. The mean maximal elimination rates (V(max)) in groups I, II, III and IV were 13.1, 11.2, 10.2 and 8.0 mg/day/kg, respectively, with statistically significant differences among groups (p=0.012, Kruskal-Wallis analysis). The intrinsic metabolic activity (V(max)/K(m)) of groups I, II, III and IV were 2.9, 2.2, 1.5 and 1.1 l/day/kg, respectively (p=0.009), again with significant differences among groups. These findings indicate that polymorphism of CYP2C9 and CYP2C19 plays an important role in phenytoin metabolism in children. With a total processing time for this assay of less than 3 hours, prediction of the optimal phenytoin dosage based on the CYP2C9 and CYP2C19 genotypes will be possible before commencement of therapy, resulting in the prevention of phenytoin overdoses in pediatric patients with epilepsy.
细胞色素P450 2C9（CYP2C9）和细胞色素P450 2C19（CYP2C19）的基因多态性导致某些抗癫痫药物药代动力学的个体差异，这是广为人知的。我们使用Light Cycler（®）聚合酶链反应（PCR）系统开发了一种快速检测CYP2C9和CYP2C19基因多态性的方法。利用该方法，我们检测了20例因癫痫而服用苯妥英钠的日本儿科患者的基因多态性，并将其基因多态性分为四组：第一组，CYP2C9*1/1和CYP2C191/1；第二组，CYP2C91/1和CYP2C191/2或1/3；第三组，CYP2C91/1和CYP2C192/2；第四组，CYP2C91/3和CYP2C191/2或1/*3。第一、二、三、四组的平均最大消除率（V(max)）分别为13.1、11.2、10.2和8.0 mg/天/千克，组间差异有统计学意义（p = 0.012，Kruskal-Wallis分析）。第一、二、三、四组的内在代谢活性（V(max)/K(m)）分别为2.9、2.2、1.5和1.1升/天/千克（p = 0.009），组间差异同样有统计学意义。这些发现表明，CYP2C9和CYP2C19的基因多态性在儿童苯妥英钠代谢中起重要作用。由于该检测的总处理时间不到3小时，因此在治疗开始前就可以根据CYP2C9和CYP2C19基因型预测苯妥英钠的最佳剂量，从而预防癫痫儿科患者苯妥英钠过量。
