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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(T_(1/2)=18.09h)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8h和18.75h,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。
AIM: To investigate the pharmacokinetics, tissue distribution and excretion of Bis (9) - (-) - Meptazinol (B9M), a novel acetylcholinesterase (AChE) inhibitor, in mice and rats. Methods: The LC-MS / MS quantitative method of B9M in rat plasma was used to detect the contents of plasma and brain tissue of mice after subcutaneous and intravenous administration of B9M. The corresponding pharmacokinetic parameters were calculated, Tissue distribution and excretion in feces and urine of B9M mice (1.5 mg / kg) and rats (1.0 mg / kg) were measured at different time points after subcutaneous administration. Results: After the mice were injected subcutaneously, the B9M could rapidly enter the blood (Tmax = 0.25 h) and the elimination rate was slower (T 1/2 = 18.09 h). The absolute bioavailability was 115.95%. After subcutaneous injection, the peak time and half-life of B9M in the brain were 8h and 18.75h respectively, and the bioavailability was 44.67%. Mice and rats are widely distributed in various tissues after subcutaneous administration, with the largest distribution of blood, such as spleen, lung and kidney. Excretion of B9M from the body The rapid release of prototype drugs in the urine and feces of mice and rats excreted less than 3%. Conclusion: The subcutaneous administration of B9M has the characteristics of easy absorption, wide distribution and easy excretion in mice and rats with excellent pharmacokinetic characteristics and is a promising new drug for Alzheimer’s disease (AD) .