| 史玉欢 赵恒毅 葛新星 郑兆浠 王宇 谢琼 仇缀百 王昊.新型乙酰胆碱酯酶抑制剂Bis(9)-(-)-Meptazinol的小鼠
和大鼠药代动力学研究[J].,2017,17(6):1001-1005 |
| 新型乙酰胆碱酯酶抑制剂Bis(9)-(-)-Meptazinol的小鼠
和大鼠药代动力学研究 |
| Pharmacokinetics of a Novel Acetylcholinesterase Inhibitor Bis(9)-(-)-Meptazinol in Mice and Rats |
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| DOI： |
| 中文关键词: Bis(9)-(-)-Meptazinol 阿尔茨海默病 药代动力学 LC-MS/MS |
| 英文关键词: Bis(9)-(-)-Meptazinol Alzheimer's disease Pharmacokinetic study LC-MS/MS |
| 基金项目:国家重大新药创制科技重大专项（2009ZX09103）；国家自然科学基金项目（81373395）；上海市科委“科技创新行动计划”生物医
药领域科技支撑项目（14431905600） |
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| 中文摘要: |
| 目的：研究新型乙酰胆碱酯酶(acetylcholinesterase，AChE)抑制剂Bis(9)-(-)-Meptazinol(B9M)在小鼠和大鼠体内的药代动力
学、组织分布和排泄过程。方法：应用本课题组前期报道的大鼠血浆中B9M的LC-MS/MS 定量方法检测B9M皮下和静脉给药后
小鼠血浆和脑组织中的含量，计算相应的药代动力学参数，测定B9M小鼠(1.5 mg/kg)和大鼠(1.0 mg/kg)皮下给药后不同时间点的
组织分布和粪便、尿液中排泄量。结果：小鼠经皮下注射后，B9M可迅速进入血液(Tmax=0.25 h)，血液中消除速度较慢(T1/2=18.09
h)，绝对生物利用度为115.95%。皮下注射后，B9M在脑内的达峰时间和半衰期分别是8 h和18.75 h，生物利用度为44.67%。小鼠
和大鼠皮下给药后广泛分布于各组织，以脾、肺、肾等血流量大的组织中分布最多。B9M从体内排泄迅速，原型药物在小鼠和大鼠
尿液和粪便中的排泄量低于3%。结论：皮下给药B9M在小鼠和大鼠体内具有易吸收、分布广泛、易排泄的特点，药代动力学特征
优良，是极具研发潜力的抗阿尔茨海默病(Alzheimer's disease，AD)新药。 |
| 英文摘要: |
| Objective:To evaluate the pharmacokinetics, tissue distribution and excretion of a novel potential acetylcholinesterase
inhibitorBis(9)-(-)-Meptazinol (B9M) inmice andrats after subcutaneous administration.Methods:ALC-MS/MSmethod previouslyreported
by our group was used to determine the concentration of B9M in plasma and brain to calculate the pharmacokinetic parameters of B9M
in mice, and the concentration of B9M in different tissues, urine and feces to assess the distribution and excretion patterns of B9M in
mice and rats.Results:After subcutaneous administration, B9M was quickly absorbed from the subcutaneous tissues into plasma with a
Tmax of 0.25 h, and slowly eliminated fromthe plasma with a T1/2 of 18.09 h. The absolute bioavailability of B9M was 115.95%in mice
plasma. The Tmax and T1/2 of B9Min mice brain was 8 h and 18.75 h respectively. The absolute bioavailability was 44.67%. B9M was
well distributed to the tissues in both mice and rats and it was mainly enriched in spleen, lung, and kidney. B9M was excreted from the
body rapidly. Less than 3% of unchanged B9M was excreted in the urine and feces of mice and rats.Conclusion:B9M was well
absorbed, widely distributed and rapidly excreted after subcutaneous administration in the mice and rats. The good pharmacokinetics
characters of B9Msuggested its significant research and development value for the treatment of Alzheimer's disease. |
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