目的 表征开心散各成分在寡聚态β淀粉样蛋白1-42（β amyloid protein 1-42，Aβ_1-42）诱导阿尔茨海默症（Alzheimer’s disease，AD）模型大鼠体内的药动学行为，建立并验证同时测定大鼠血浆中开心散各成分含量的超高效液相色谱-串联质谱（UPLC-MS/MS）方法。方法 采用双侧海马注射寡聚态Aβ_1-42的方法建立AD大鼠模型，开心散单次ig给药，于不同时间点取血，测定各成分的血药浓度。采用DAS 2.0软件以非房室模型拟合，计算药动学参数。结果 建立的UPLC-MS/MS方法的精密度、准确度、提取回收率、基质效应和稳定性等方法学考察结果均符合生物样品分析的测定要求。Morris水迷宫实验证实成功构建AD大鼠模型（P＜0.05）。AD模型大鼠给予开心散后，按中药化学结构分类的同型化合物具有相似的药动学特征，如属于同分异构体的α-细辛醚和β-细辛醚、同属于羊毛甾-7,9(11)-二烯型三萜的去氢土莫酸与松苓新酸以及同属于3,4-开环-羊毛甾-7,9(11)-二烯型三萜的茯苓新酸A和茯苓新酸B等。α-细辛醚和β-细辛醚的达峰时间（t_max）和消除半衰期（t_1/2）均较短，表明二者在AD模型大鼠体内吸收迅速，消除也快；茯苓新酸A和茯苓新酸B的达峰时间（t_max）较短，但二者的半衰期（t_1/2）却较长，表明它们吸收迅速，但消除缓慢。去氢土莫酸和松苓新酸达峰时间（t_max）和半衰期（t_1/2）均较长，吸收和消除缓慢。此外，去氢土莫酸的药时曲线存在双峰现象，其平均滞留时间（MRT）也较长，这可能源于较强的肝肠循环，延长了其作用时间。结论 揭示了AD疾病状态下开心散的体内药动学过程，为阐明开心散成分体内过程及其后续研究开发提供参考。

Objective To characterize the pharmacokinetic behavior of the analytes of Kaixin Powder (开心散) in Alzheimer's disease (AD) rats induced by oligomeric β amyloid protein 1-42 (Aβ_1-42), and establish and verify an ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for simultaneous determination of components of Kaixin Powder in rat plasma. Methods Rats model of AD was established by bilateral hippocampal injection of oligomeric Aβ_1-42. Kaixin Powder was administered by single ig, blood was collected at different time points, and plasma concentrations of ingredients were determined. DAS 2.0 software was used to fit non-compartmental models to calculate pharmacokinetic parameters. Results The established UPLC-MS/MS method in terms of precision, accuracy, extraction recovery, matrix effect and stability and other methodological investigation results all met the determination requirements of biological sample analysis. The results of Morris water maze test confirmed that AD rats model was successfully constructed (P < 0.05). After administration of Kaixin Powder, pharmacokinetic parameters of analytes with similar structure were similar, such as α-asarone and β-asarone belonging to isomers, dehydrotumulosic acid and dehydrotrametenolic acid belonging to lanosta-7,9(11)-diene type triterpenes, poricoic acid A and poricoic acid B belonging to 3,4-seco-lanostan-7,9(11)- diene type triterpenes. t_max and t_1/2of α-asarone and β-asarone were short which showed a rapid absorption and elimination. t_max of poricoic acid A and poricoic acid B were short but t_1/2 of them were long, suggesting a rapid absorption and slow elimination; t_max and t_1/2 of dehydrotumulosic acid and dehydrotrametenolic acid were long, so the absorption and elimination rates of these compounds were slow. Moreover, dehydrotumulosic acid played a double-peak phenomenon and MRT of it was long. This might be caused by the enterohepatic circulation, and time of dehydrotumulosic acid in vivo could be prolonged. Conclusion The in vivo pharmacokinetic process of the analytes of Kaixin Powder in AD rats is revealed, which can provide reference for clarifying the in vivo process of Kaixin Powder and its subsequent research and development.

北京市自然科学基金面上项目(7182019);北京市青年拔尖人才培育计划项目(CIT&TCD201504098)