摘要/Abstract
摘要： 目的·研究新型多靶点胆碱酯酶抑制剂氨基甲酰酯-查尔酮衍生物DDDA3的药代动力学特征，为DDDA3的体内抗阿尔茨海默病（Alzheimers disease, AD）活性评价及制剂开发提供实验依据。方法·建立并验证了一种高效液相色谱-串联质谱（high performance liquid chromatography-tandem mass spectrometry，HPLC-MS/MS）测定DDDA3的方法，并将该方法应用于大鼠体内DDDA3的药代动力学研究。采用蛋白质沉淀法制备血浆样品，通过样品浓缩降低检测限。运用Zorbax SB-Aq色谱柱（2.1 mm×100 mm，3.5 μm）分离DDDA3，流动相由甲醇和水相（体积比为75:25）组成，水相中含有0.1%的甲酸和10 mmol/L的甲酸铵。采用电喷雾离子源，在正离子模式下进行多反应监测。结果·此方法定量下限为0.5 ng/mL，线性范围为0.5～500 ng/mL。DDDA3在SD大鼠体内的绝对口服生物利用度为78.4%。结论·DDDA3口服生物利用度高，口服吸收快，血药浓度维持时间长，具有较好的抗AD开发潜力，但仍需优化制剂工艺，改善水溶性。
关键词: DDDA3, 阿尔茨海默病, 高效液相色谱-质谱联用, 药代动力学, 血浆, 大鼠
Abstract:
Objective · To perform the pharmacokinetic (PK) studies of DDDA3, a dual inhibitor of both acetylcholinesterase and butyrylcholinesterase, into provide experimental evidence for the evaluation of in vivo activity against Alzheimers disease (AD) and the formulation optimization. Methods · A high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for the quantification of DDDA3 was developed and validated. This method was applied to pharmacokinetic studies of DDDA3 in rat plasma. Protein precipitation approach was used to prepare plasma samples. To lower the detection limit, the concentration step was utilized. The samples were analyzed on a Zorbax SB-Aq column (2.1 mm×100 mm, 3.5 μm) with the mobile phase composed of methanol and water (75:25volume, containing 0.1% formic acid and 10 mmol/L ammonium formate) and determinedpositive electrospray ionization in multiple reaction monitoring mode. Results · The lower limit of quantification was 0.5 ng/mL and the linear range was 0.5-500 ng/mL. The absolute oral bioavailability of DDDA3 in SD rats was 78.4%. Conclusion · DDDA3 has high potentials as anti-AD agents, with good oral bioavailability, fast absorption rate, and long-lasting blood concentration; however, the formulation should be optimized to improve the solubility.
Key words: DDDA3, Alzheimer&, rsquo, s disease, high performance liquid chromatography-tandem mass spectrometry, pharmacokinetics, plasma, rat
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