| 谭小芳,李馨敏,郑 伟,李 娟,唐亚斌.LC-MS/MS测定小鼠血浆中多靶点抗AD bis-MEP-乙二酰胺杂合物ZLA浓度及药动学研究[J].,2018,(1):6-11 |
| LC-MS/MS测定小鼠血浆中多靶点抗AD bis-MEP-乙二酰胺杂合物ZLA浓度及药动学研究 |
| Determination of Plasma Concentrations and Pharmacokinetic Parameters of a Multi-target Anti-AD Agent in Mice by LC-MS/MS |
| 投稿时间：2017-10-20 修订日期：2017-11-12 |
| DOI：10.13241/j.cnki.pmb.2018.01.002 |
| 中文关键词: ZLA 阿尔茨海默病 LC-MS/MS 药代动力学 小鼠血浆 |
| 英文关键词: N1,N2-bis(3-(S)- meptazinol- propyl) oxalamide Alzheimer's disease LC-MS/MS Pharmacokinetics Mouse plasma |
| 基金项目:国家自然科学基金项目（81373417，30973538，21202098，81573018）；上海市"科技创新行动计划"生物医药领域科技支撑项目（14431901800）；上海市青年科技英才-扬帆计划项目（15YF1406700） |
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| 中文摘要: |
| 摘要 目的：建立检测小鼠血浆内新型多靶点抗阿尔茨海默病（Alzheimer's disease，AD）药物双美普他酚-乙二酰胺杂合物（ZLA）浓度的高效液相色谱-质谱联用法(LC-MS/MS)，并研究其在小鼠体内的药代动力学。方法：样品经甲醇沉淀去蛋白，应用Waters Xbridge C18色谱柱（2.1×100 mm，3.5 μm），以甲醇- 水（含5 mM甲酸铵，pH 9.8）（85:15，v/v）为流动相，流速0.25 mL/min；采用电喷雾（ESI）离子源，选择正离子模式多反应监测，待测物分别为m/z 304.3→107.0（ZLA）和m/z 621.7→232.1（内标）。分别给予KM小鼠腹腔和尾静脉注射ZLA 5mg/kg，不同时间点采集血浆用于ZLA定量分析。结果：ZLA和内标保留时间分别为3.2 min和 2.5 min。血浆中ZLA线性范围为1-1000 ng/mL。血浆中提取回收率超过91%，日内和日间精密度RSD均小于6%。药动学研究结果显示，腹腔注射时ZLA可快速分布到血浆中，在10.2 min达到峰值，且能达到良好的生物利用度（47.6%）。结论：本研究建立的ZLA血药浓度测定方法快速、灵敏，特异性好，并成功应用于小鼠血浆中ZLA的药代动力学研究。本研究资料将为ZLA在AD治疗中的进一步临床前评估提供依据。 |
| 英文摘要: |
| ABSTRACT Objective: To develop an LC-MS/MS method for the quantitative analysis of plasma concentrations of N1, N2-bis(3-(S)- meptazinol- propyl) oxalamide (ZLA), a new multi-target-directed agent for Alzheimer's disease (AD), and for study of its pharmacoki- netic profile. Methods: Plasma samples of mice were pretreated with methanol for protein precipitation. The analytes were separated on a Waters Xbridge C18 column (2.1×100 mm, 3.5 μm) with a mobile phase consisting of methanol and water (containing 5 mM ammoni- um formate, pH 9.8) (85:15, v/v) and detected by positive electrospray ionization in multiple reaction monitoring (MRM) mode. MRM transitions were m/z 304.3→107.0 (ZLA) and m/z 621.7→232.1 (internal standard, IS), respectively. In the pharmacokinetic study, mice received intravenous or intraperitoneal ZLA (5 mg/kg) administration. The plasma samples were collected at different time points for analysis. Results: The retention time of ZLA and IS was 3.2 min and 2.5 min, respectively. The linear ranges of ZLA in plasma were 1-1000 ng/mL. The extraction recovery of ZLA in plasma was over 91%. The relative standard deviation of intra-day and inter-day varia- tion was 3.1-5.9% and 4.6-5.1%, respectively. Pharmacokinetic studies revealed that ZLA reached peak concentration rapidly after in- traperitoneal administration (Tmax=10.2 min) and exhibited a satisfying bioavailability(47.6%). Conclusion: A specific and sensitive method was firstly reported for the quantification of ZLA, a novel candidate for multi-targeted AD therapy. This method was successfully applied to explore the pharmacokinetic profiles of ZLA in mice plasma. These data may be essential for the further preclinical evaluation of ZLA in AD therapy. |
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