大鼠急性经皮暴露毒死蜱的生理药动学和药效学模型研究

发布时间：2019-07-26 16:28

【摘要】：目的 :构建经皮暴露毒死蜱的药动学和药效学模型(physiologically based pharmacokinetic and pharmacodynamic model,PBPK/PD model)。方法 :1动物实验:成年雌性SD大鼠按体重随机分成3个剂量组和1个对照组,一次性皮下注射毒死蜱,各组在3、6、12、24、48、72 h 6个时间点收集大鼠生物样本。测定指标包括血清毒死蜱(CPF)、血清和尿液3,5,6-三氯-2-吡啶(TCP),以及血清胆碱酯酶(cholinesterase,CHE)包括乙酰胆碱酯酶(acetylcholinesterase,ACh E)和丁酰胆碱酯酶(butyrylcholinesterase,Bu Ch E);2模型建立:确定模型房室结构;建立微分方程,搜集参数;模型模拟,并根据动物实验数据优化模型参数;模型验证。结果:根据139.5 mg/kg组动物实验数据得到优化的PBPK/PD模型,然后用此模型模拟69.75 mg/kg和279.00 mg/kg组的CPF、TCP、ACh E和Bu CHE时量变化,得到该模型的模拟效果较好。实验和模型模拟结果都显示血清CPF和TCP在体内呈先上升后下降趋势,血清Ch E活性呈先下降后上升趋势。实验数据显示各剂量组血CPF浓度在染毒后6 h达峰值,血TCP浓度在12~24 h达峰,血ACh E在24 h抑制最大,血Bu Ch E在12~24 h抑制最大,模型模拟数据显示血CPF在6.7 h达峰,血TCP浓度在24.7 h达峰,血ACh E在32~35 h抑制最大,血Bu Ch E在15~28 h抑制最大。结论:本研究构建的PBPK/PD模型可以较好地模拟CPF、TCP和Ch E在体内的动态代谢过程。
[Abstract]:Objective: to construct the pharmacokinetics and pharmacokinetics model (physiologically based pharmacokinetic and pharmacodynamic model,PBPK/PD model). Of transdermal exposure to chlorpyrifos. Methods: 1 Animal experiment: adult female SD rats were randomly divided into 3 dose groups and 1 control group according to their body weight. Chlorpyrifos was injected subcutaneously in each group. Biological samples were collected at 3, 6, 12, 24, 48, 72 h. The indexes included serum chlorpyrifos (CPF), serum and urine 3, 5, 6-trichloro-2-pyridine (TCP), and serum cholinesterase (cholinesterase,CHE), including acetylcholinesterase (acetylcholinesterase,ACh E) and butyrylcholinesterase (butyrylcholinesterase,Bu Ch E); 2). The model was established to determine the atrioventricular structure of the model; to establish differential equation and collect parameters; to simulate the model and optimize the model parameters according to the animal experimental data; and to verify the model. Results: according to the experimental data of 139.5 mg/kg group, the optimized PBPK/PD model was obtained, and then the CPF,TCP,ACh E and Bu CHE time changes of 6.975 mg/kg and 279.00 mg/kg groups were simulated by this model, and the simulation effect of the model was better. The results of experiment and model simulation showed that serum CPF and TCP increased at first and then decreased, and serum Ch E activity decreased at first and then increased. The experimental data showed that the concentration of blood CPF reached the peak at 6 h after exposure, the concentration of blood TCP reached the peak at 12 鈮，

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