癫痫患者丙戊酸与拉莫三嗪药代动力学相互作用研究  

Pharmacokinetic interaction between valproic acid and lamotrigine in Chinese patients with epilepsy

作　　者：张晓旭 陈子怡[2] 任瑞娜 李蕊彤 王雪丁[1] 倪冠中[2] 周亚芳[1] 戴启麟[2] 周列民[2] 黄民[1] ZHANG Xiao-xu;CHEN Zi-yi;REN Rui-na;LI Rui-tong;WANG Xue-ding;NI Guan-zhong;ZHOU Ya-fang;DAI Qi-lin;ZHOU Lie-min;HUANG Min(Institute of Clinical Pharmacology,School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510080,Guangdong Province,China;Department of Neurology,The First Affiliated Hospital,Sun Yat-sen University,Guangzhou 510080,Guangdong Province,China)

机构地区：[1]中山大学药学院临床药理研究所,广东广州510080 [2]中山大学附属第一医院神经内科,广东广州510080

出　　处：《中国临床药理学杂志》2021年第1期66-69,共4页The Chinese Journal of Clinical Pharmacology

基　　金：国家自然科学基金资助项目(81730103,81973398,81473283,81573507);国家重点研发计划基金资助项目(2017YFC0909303,2016YFC0905001);广东省自然科学基金资助项目(201607020031)。

摘　　要：目的考察癫痫患者合用丙戊酸(VPA)与拉莫三嗪(LTG)的药代动力学相互作用。方法将纳入的癫痫患者随机分为3组:VPA组276例、LTG组254例和合用组334例。VPA组患者每天口服VPA 500~1000 mg,LTG组每天口服LTG 100~200 mg,合用组用VPA+LTG。高效液相色谱-质谱联用法测定VPA及其主要代谢产物及LTG晨间稳态谷浓度,分析两药单用与合用的血药浓度变化情况。结果合用组和LTG组的LTG血药浓度中位数及四分位数分别为3.26[2.51-4.10](μg·mL^-1)·(mg·kg^-1)^-1和1.23[0.90-1.60](μg·mL^-1)·(mg·kg^-1)^-1,组间比较差异有统计学意义(P<0.0001),且呈剂量相关关系。合用组:VPA的主要代谢产物3-keto-VPA、3-OH-VPA、4-OH-VPA、4-ene-VPA和5-OH-VPA的体重剂量校正浓度的中位数及四分位数均显著高于VPA组,差异有统计学意义(P<0.0001);但VPA原型及其代谢产物2-ene-VPA的血药浓度差异无统计学意义。结论合用组可显著升高LTG血药浓度,且呈剂量相关性;表明合用LTG可显著升高VPA主要代谢产物的血药浓度。Objective To investigate the pharmacokinetic interaction between valproic acid(VPA)and lamotrigine(LTG)in epileptic patients.Methods The epilepsy patients were randomly divided into three groups:VPA group(276 cases),LTG group(254 cases)and VPA combined with LTG group(334 cases).Patients in the VPA group and LTG group were given oral administration VPA of 500-1000 mg·d^-1 and LTG of 100-200 mg·d^-1.VPA combined with LTG group were VPA+LTG.The morning trough plasma concentrations of VPA and its major metabolites and LTG were determined by HPLC-MS/MS method to analyze the change of serum concentration of two drugs used alone or in combination.Results The median,25%,and 75%quartiles of LTG concentration to weight adjusted dose ratio(CDR)in combination therapy with VPA group were significantly higher than that of LTG group(3.26[2.51-4.10](μg·mL^-1)·(mg·kg^-1)-1 vs 1.23[0.90-1.60](μg·mL^-1)·(mg·kg^-1)-1,P<0.0001).The CDR of 3-keto-VPA,3-OH-VPA,4-OH-VPA,4-ene-VPA and 5-OH-VPA were significantly higher than those of VPA group(P<0.0001).However,there was no significant difference in plasma concentrations of VPA prototype and its metabolite 2-ene-VPA.Conclusion The combination of VPA with LTG can significantly increase LTG,CDR with a dose-related relationship,and combining LTG can significantly increase the CDR of VPA major metabolites.

关 键 词：拉莫三嗪 丙戊酸 血药浓度 相互作用 高效液相色谱-质谱联用法 

分 类 号：R971.6[医药卫生—药品]