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。
Objective：To build PBPK/PD models subcutaneous exposured to chlorpyrifos. Methods： （1）Animalt：Aduh female SD rats were randomly divided into 3 treated groups and 1 control group. Subcutaneous injection was performed for once,and biological samples were collected at 3,6, 12,24,48,72 hours. The indicators included serum CPF,TCP and urine, serum acetylcholinesterase （ACHE） and butyrylcholinesterase （BuChE）. （2） The establishment of models： a： Determination the model structure, b ：Set up of differential equation,and collection the parameters of model, c：Simulation. Optimize the model parameters, d：Validation of models. Results：The PBPK/PD model parameters was optimized according to experimental data of 139.5 mg/kg group. Changes of CPF,TCP and ChE were mocked in this model, and the simulation results were good. The experiments and model simulation results showed that CPF and TCP in serum increased initially and then decreased. ChE activity in serum decreased initially and then increased. Experimental data showed that serum CPF and TCP reached peak at 6-hour and 12-24-hour after exposure,respectively. Serum AChE and BuChE activity achived the minimum at 24-hour and 12-24-hour,respectively. Model simulation data showed that serum CPF and TCP reached peak at 6.7-hour and 24.7-hour,respectively. Serum AChE and BuChE activity achived the minimum at 32-35-hour and 15-28-hour,respectively. Conclusion：PBPK/PD models can simulate the disposal process of CPF,TCP and ChE.
出处
《南京医科大学学报（自然科学版）》
CAS
CSCD
北大核心
2015年第5期745-750,共6页
Journal of Nanjing Medical University(Natural Sciences)
基金
国家自然科学基金(81273080
81072304)
