大鼠灌胃朱砂与复方牛黄消炎胶囊后汞的药代动力学研究

宋晓妮　陆宇婷　杨丹亿　汪生　杭太俊　宋敏

[摘要]復方牛黄消炎胶囊作为清热解毒、镇静消炎的经典复方，朱砂是其发挥药效的主要成分之一。该实验采用HNO3HClO4消解体系结合冷原子原子荧光光谱（CVAFS）分析技术检测大鼠全血中的汞元素。研究大鼠灌胃给药不同剂量朱砂和复方牛黄消炎胶囊后，全血中汞的药代动力学行为，探讨中药复方配伍对汞体内代谢过程的影响。研究发现大鼠灌胃高、中、低3个剂量朱砂和复方牛黄消炎胶囊后，全血中汞均呈非线性药代动力学特征。大鼠灌胃复方牛黄消炎胶囊后，与单味朱砂相比，全血中汞元素的tmax，Ke，CL/F显著降低，Cmax/dose，AUC/dose，t1/2显著增加，Vz/F，MRT不存在显著差异，提示经复方配伍后，汞元素在全血中吸收的总量显著增加且吸收速度加快，但消除速度减慢，提示长期服用可能会引起汞在体内的蓄积。

[关键词]朱砂； 复方牛黄消炎胶囊； 汞； 全血； 冷原子原子荧光光谱（CVAFS）

[Abstract]Fufang Niuhuang Xiaoyan capsule was a classical compound prescription with the efficacy of heatclearing， detoxification， sedation and antiinflammation， with cinnabaris as one of its active ingredients The study focuses on the pharmacokinetics of mercury in rats after oral administration of cinnabaris and Fufang Niuhuang Xiaoyan capsule， in order to explore the effect of combined traditional Chinese medicines on mercury metabolism In this study， the method of nitricperchloric acid digestion system coupled with cold atomicatomic fluorescence spectroscopy （CVAFS） was adopted to accurately determine mercury in whole blood of rats Fufang Niuhueng Xiaoyan capsule had three dose schemes of oral administration， namely equivalent clinical dose， 3 times of equivalent clinical dose and 10 times of equivalent clinical dose； And the doses of oral administration of cinnabaris was calculated according to that of Fufang Niuhuang Xiaoyan capsule SPF grade healthy SD rats were fasted overnight before the oral administration with cinnabaris suspension （or Fufang Niuhuang Xiaoyan capsule suspension） After oral administration of different doses of cinnabaris， no obvious changes in tmax and MRT were observed， while Cmax/dose， AUC048 h/dose and AUC0∞/dose decreased with the increase in dose， indicating that total mercury absorption in body was declining As the dose increased， Ke， CL/F decreased， and t1/2 increased， indicating that the elimination slowed down， and mercury metabolism showed nonlinear dynamic characteristics within a certain range of dose （22220 mg·kg-1） The total mercury metabolism in the whole blood of rats after oral administration with different doses of Fufang Niuhuang Xiaoyan capsule also showed nonlinear dynamic characteristics The results were correlated with the low solubility of cinnabaris in the body Compared with cinnabaris， Fufang Niuhuang Xiaoyan capsule showed no obvious changes in V/F and MRT， while Ke， CL/F， tmax decreased， and t1/2， Cmax/dose， AUC048 h/dose， AUC0∞/dose increased significantly The results showed that Fufang Niuhuang Xiaoyan capsule accelerated absorption， slowed down elimination and improved the total absorption of mercury in the whole blood， indicating that Fufang Niuhuang Xiaoyan capsule may contain components for promoting absorption and alleviating elimination of mercury Fufang Niuhuang Xiaoyan capsule had an impact on the pharmacokinetics of cinnabaris， and longterm administration of cinnabaris （Fufang Niuhuang Xiaoyan capsule） was possible to cause accumulation of mercury in the body This study could explain changes in efficacy of Fufang Niuhuang Xiaoyan capsule， evaluate the rationality of compound medicines containing toxic elements and provide scientific basis for the rational and safe use of Fufang Niuhuang Xiaoyan capsule

[Key words]cinnabaris； Fufang Niuhuang Xiaoyan capsule； mercury； blood； cold atomfluorescence spectroscopy （CVAFS）

复方牛黄消炎胶囊（Fufang Niuhuang Xiaoyan capsule）作為清热解毒、镇静消炎的中成药，历经数百年的流传应用，发展成为目前《中国药典》收载的由人工牛黄、黄芩、栀子、朱砂、珍珠母、郁金、雄黄、冰片、石膏、水牛角浓缩粉、盐酸小檗碱11味中药加工成的复方制剂[1]。作为含汞（朱砂）的中成药，其用药的安全性值得关注，因服用含朱砂中成药而发生的中毒事件时有发生[23]。由此可见，探讨中成药中复方配伍对汞代谢的影响是十分有必要的。

目前，对于中药中朱砂的的研究主要针对单味朱砂的慢性毒性研究[4]，但对朱砂中汞的药代动力学报道较少[5]，仅进行朱砂高剂量单次给药试验[6]，对中药复方配伍对汞体内代谢变化的影响未见报道。……