项目名称： 采用“多器官-在线微透析-LC/MS/MS”技术的百草枯大鼠器官毒代动力学模型和毒性关系研究

项目编号： No.81501655

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 李鹏飞

作者单位： 首都医科大学

项目金额： 18万元

中文摘要： 百草枯中毒在我国发生率高，口服死亡率高达90%以上，中毒征象波及多器官系统，无有效解毒药。通过服毒量、中毒时间、血液百草枯浓度、临床检查等不能准确评估急性百草枯中毒患者的预后和生存率。开展百草枯毒理学和毒代动力学研究是急诊医学百草枯中毒解救的迫切需求。课题组提出采用“多器官-在线微透析-LC/MS/MS”技术系统地研究百草枯大鼠器官毒代动力学规律和毒性关系。建立多剂量百草枯中毒模型，创建“肺-肝-肾-血液”四联微透析同步取样技术，联合高效液相串联质谱，能够准确考察百草枯中毒后靶器官毒代动力学过程，明确靶器官百草枯毒代动力学参数和消除动力学模型。通过直接确证动物器官的实际暴露水平与染毒变量的关系，建立四器官权重的百草枯中毒严重指数和生存概率综合效应评价方法。研究最终可为临床百草枯急救中的医学评价和诊断提供实验依据和实验方法，也可为百草枯解毒药的临床前毒理和药效研究提供研究方法和评价方法。

中文关键词： 百草枯；中毒；器官毒代动力学；液相色谱串联质谱；微透析

英文摘要： It is the high incidence in China with mortality rate of oral paraquat poisoning more than 90%. Poisoning signs involve multiple organ system. There is no antidote till now. The accurate evaluation of the prognosis of patients with paraquat poisoning can’t be achieved through measuring dose of poison, time of poisoning and concentration of paraquat in blood. The clinical examinations can’t also used for forecasting the prognosis of patients with paraquat poisoning and survival rate. It is the imperious demands of poisoning rescue of paraquat in emergency medicine by research of toxicity and toxicokinetics. Hypothesis formulation is now put forward to research the rule of physiological toxicokinetics of paraquant systematically through multi-organ online-microdialysis LC/MS/MS technique. The investigation of toxicokinetic process in vivo, toxicokinetics parameters and eliminate dynamic model will be carried out through setting up multi-dose single-pass paraquant poisoning model and applying “lung- liver - kidney -blood” four points microdialysis sync sampling technique combined with LC/MS/MS technique. It is aimed to establish the way of the weight index of four-organs and the evaluation of integrated effects of survival probability. The research will finally provide the method of investigation and evaluation for study of preclinical toxicology of paraquat antidote. Meanwhile, it also provides evidence for medical evaluation and diagnosis during emergency treatment.

英文关键词： paraquat;poisoning;organ toxicokinetics;LC/MS/MS;microdialysis