【摘要】：目的 :構(gòu)建經(jīng)皮暴露毒死蜱的藥動學和藥效學模型(physiologically based pharmacokinetic and pharmacodynamic model,PBPK/PD model)。方法 :1動物實驗:成年雌性SD大鼠按體重隨機分成3個劑量組和1個對照組,一次性皮下注射毒死蜱,各組在3、6、12、24、48、72 h 6個時間點收集大鼠生物樣本。測定指標包括血清毒死蜱(CPF)、血清和尿液3,5,6-三氯-2-吡啶(TCP),以及血清膽堿酯酶(cholinesterase,CHE)包括乙酰膽堿酯酶(acetylcholinesterase,ACh E)和丁酰膽堿酯酶(butyrylcholinesterase,Bu Ch E);2模型建立:確定模型房室結(jié)構(gòu);建立微分方程,搜集參數(shù);模型模擬,并根據(jù)動物實驗數(shù)據(jù)優(yōu)化模型參數(shù);模型驗證。結(jié)果:根據(jù)139.5 mg/kg組動物實驗數(shù)據(jù)得到優(yōu)化的PBPK/PD模型,然后用此模型模擬69.75 mg/kg和279.00 mg/kg組的CPF、TCP、ACh E和Bu CHE時量變化,得到該模型的模擬效果較好。實驗和模型模擬結(jié)果都顯示血清CPF和TCP在體內(nèi)呈先上升后下降趨勢,血清Ch E活性呈先下降后上升趨勢。實驗數(shù)據(jù)顯示各劑量組血CPF濃度在染毒后6 h達峰值,血TCP濃度在12~24 h達峰,血ACh E在24 h抑制最大,血Bu Ch E在12~24 h抑制最大,模型模擬數(shù)據(jù)顯示血CPF在6.7 h達峰,血TCP濃度在24.7 h達峰,血ACh E在32~35 h抑制最大,血Bu Ch E在15~28 h抑制最大。結(jié)論:本研究構(gòu)建的PBPK/PD模型可以較好地模擬CPF、TCP和Ch E在體內(nèi)的動態(tài)代謝過程。
[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，

本文編號：2519663