摘要
体循环中的代谢产物常与药物的安全性或有效性密切相关,因此在开展创新药物的人体药动学研究时,除原形药物外也常测定血浆中的主要代谢产物。倍赛诺他为新型的组蛋白去乙酰化酶抑制剂,目前正处于临床开发阶段。本文建立了LC-MS/MS法同时测定人血浆中倍赛诺他和N-羟基酰胺水解代谢物M351,以评价其药动学特征。血浆样品经乙腈沉淀蛋白处理后,待测物与内源性物质在Waters ACQUITY UPLC?BEH C18柱(2.1 mm×50 mm,1.7μm)色谱分离,以乙腈-含0.2%甲酸的5 mmol·L^-1醋酸铵溶液作为流动相进行梯度洗脱。采用电喷雾电离源(ESI源),以多反应监测正离子模式检测,用于倍赛诺他和M351定量的离子对分别为m/z 367.1→235.0和m/z 352.1→207.0,同位素标记内标定量的离子对分别为m/z 371.1→235.0(d4-倍赛诺他)和357.1→208.0(d5-M351)。本方法测定血浆中倍赛诺他和M351的线性范围分别为2.00~2000 ng·m L^-1和4.00~4000 ng·m L^-1。质控样品结果显示,倍赛诺他的日内、日间精密度均不大于6.2%,准确度在-1.1%~4.3%之间;代谢物M351日内、日间精密度均不大于6.8%,准确度在-0.5%~4.9%之间。药动学结果表明,3名肿瘤患者口服100 mg倍赛诺他后,代谢物M351血浆达峰时间明显滞后于原形药物(tmax分别为4.00 h和0.67 h),达峰浓度和血浆暴露量分别约为原形药物的1.7倍和11倍,提示倍赛诺他临床研究中应关注代谢物对药物有效性和安全性的影响。本文临床实验经上海交通大学医学院附属仁济医院伦理委员会批准,并在该医院进行。
Drug metabolites in the systemic circulation can be closely related to the safety or efficacy of drugs,so it is necessary to evaluate the pharmacokinetics of both the parent drug and its major metabolites in plasma.Bisthianostat,a novel histone deacetylase(HDAC)inhibitor,is currently under development.An LC-MS/MS method was developed and validated for the simultaneous determination of bisthianostat and its hydrolyzed N-hydroxyamide metabolite M351 in human plasma to evaluate their pharmacokinetic characteristics in humans.After extraction from the plasma by acetonitrile-induced protein precipitation,the analytes and endogenous substances were separated on a Waters BEH C18column(2.1 mm×50 mm,1.7μm).The mobile phase consisted of acetonitrile and 5 mmol·L^-1ammonium acetate(containing 0.2%formic acid,v/v)for gradient elution.Positive electrospray ionization was performed using multiple reaction monitoring(MRM)with transitions of m/z 367.1→235.0 for bisthianostat,m/z352.1→207.0 for M351,m/z 371.1→235.0 for d4-bisthianostat,and m/z 357.1→208.0 for d5-M351.The method was linear over a concentration range of 2.00-2000 ng·m L^-1for bisthianostat and 4.00-4000 ng·m L^-1for M351.The results of quality control samples showed that the intra-and inter-day precision were no more than 6.2%for bisthianostat and 6.8%for M351.The accuracy ranged from-1.1%to 4.3%for bisthianostat and-0.5%to 4.9%for M351.The pharmacokinetic results show that after a single oral administration of 100 mg bisthianostat,the time to peak(tmax)of M351 in the plasma of three patients with tumors was significantly longer than that of the parent drug(tmaxwas 4.00 h and 0.67 h,respectively),and the Cmaxand plasma exposure of M351 were about 1.7times and 11 times higher,respectively,than that of the parent drug.This clinical trial was approved by the society of ethics and conducted in Renji Hospital,Shanghai Jiaotong University School of Medicine.
作者
于松达
黄洪晖
侯翔宇
沈莉菁
张仰明
南发俊
王彦
闫超
陈笑艳
YU Song-da;HUANG Hong-hui;HOU Xiang-yu;SHEN li-jing;ZHANG Yang-ming;NAN Fa-jun;WANG Yan;YAN Chao;CHEN Xiao-yan(School of Pharmacy,Shanghai Jiao Tong University,Shanghai 200240,China;Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China;Renji Hospital,Shanghai Jiaotong University School of Medicine,Shanghai 200127,China)
出处
《药学学报》
CAS
CSCD
北大核心
2020年第9期2191-2197,共7页
Acta Pharmaceutica Sinica
