Makmor-Bakry Mohd, Sills Graeme J, Hitiris Nikolas, Butler Elaine, Wilson Elaine A, Brodie Martin J
Epilepsy Unit, Section of Clinical Pharmacology & Stroke Medicine, University Division of Cardiovascular & Medical Sciences, Western Infirmary, Glasgow, Scotland.
Clin Neuropharmacol. 2009 Jul-Aug;32(4):205-12. doi: 10.1097/WNF.0b013e318187972a.
The dose of carbamazepine required to achieve optimal seizure control varies widely from patient to patient. We investigated polymorphic variants in various genes involved in the pharmacokinetics and pharmacodynamics of carbamazepine in an effort to identify predictors of maintenance dose.
: A total of 70 patients with epilepsy (49% were males; median age, 34 years; range, 14-72 years) who had benefited (>50% reduction in seizure frequency for at least 12 months) from treatment with carbamazepine monotherapy were included in the analysis. Known variants in drug-metabolizing enzyme genes, including those encoding cytochrome P450s, uridine 5'-diphosphate-glycosyltransferase, and microsomal epoxide hydrolase, together with a sodium channel polymorphism in SCN2A, were screened using polymerase chain reaction-restriction fragment length polymorphism or direct sequencing. Associations between demographic and genetic variables and carbamazepine dose were identified by univariate and multivariate regression analyses.
All genotype frequencies were consistent with Hardy-Weinberg equilibrium (P > 0.05). No single demographic or genetic variable was of sufficient strength to independently influence carbamazepine dosing requirements. However, a multivariate model, incorporating patient age and specific genotypes (c.337T>C, c.416A>G) of the EPHX1 gene encoding microsomal epoxide hydrolase, revealed a significant association with the maintenance dose of carbamazepine (r(2) = 0.362, P= 0.002).
This proof-of-principle study suggests that genetic variants in EPHX1 can be used to predict maintenance doses of carbamazepine. A large-scale prospective investigation of genetic influences on drug dosing strategies in epilepsy, with specific focus on whole gene variability for those proteins involved in the pharmacokinetics and pharmacodynamics of antiepileptic agents, is warranted.
实现最佳癫痫发作控制所需的卡马西平剂量在患者之间差异很大。我们研究了参与卡马西平药代动力学和药效学的各种基因中的多态性变异，以确定维持剂量的预测因素。
分析纳入了70例癫痫患者（49%为男性；中位年龄34岁；范围14 - 72岁），这些患者接受卡马西平单药治疗后病情改善（癫痫发作频率至少降低50%达12个月以上）。使用聚合酶链反应 - 限制性片段长度多态性或直接测序法，筛查药物代谢酶基因中的已知变异，包括编码细胞色素P450s、尿苷5'-二磷酸 - 糖基转移酶和微粒体环氧化物水解酶的基因，以及SCN2A中的钠通道多态性。通过单因素和多因素回归分析确定人口统计学和基因变量与卡马西平剂量之间的关联。
所有基因型频率均符合哈迪 - 温伯格平衡（P > 0.05）。没有单一的人口统计学或基因变量有足够强度独立影响卡马西平的给药需求。然而，一个纳入患者年龄和编码微粒体环氧化物水解酶的EPHX1基因的特定基因型（c.337T>C、c.416A>G）的多因素模型显示，与卡马西平的维持剂量有显著关联（r(2) = 0.362，P = 0.002）。
这项原理验证研究表明，EPHX1基因中的遗传变异可用于预测卡马西平的维持剂量。有必要对癫痫药物给药策略的遗传影响进行大规模前瞻性研究，特别关注抗癫痫药物药代动力学和药效学相关蛋白质的全基因变异性。
