柴苓舒肝丸药物代谢动力学及毒理学的研究

Study on pharmacokinetics and toxicology of Chailing Shugan Pills

目的探讨柴苓舒肝丸(原柴苓清肝丸)的体内药动学特点及脏器毒性。方法60只大鼠随机分为对照组、模型组、阳性药组及中药组,对照组正常饲养,其余组建立大鼠抑郁模型,在此基础上,阳性药组及中药组分别采用氟西汀和柴苓舒肝丸悬浊液灌胃,持续6个月。中药组大鼠在清醒状态下按照预定时间自锁骨下颈静脉采集血液,用UPLC-MS/MS法测定血浆中柴胡皂苷D和黄芪甲苷的含量,了解在单次给药和多次给药后的药代动力学特征。灌胃6个月后处死剩余大鼠,解剖主要组织器官,精密称量、计算脏器指数,同时苏木精-伊红染色法(HE)染色观察各组织器官病理改变情况。结果大鼠在单次给药和多次给药后,柴胡皂苷D的半衰期(t_(1/2))分别为2.07 h、2.27 h,清除率(CL)分别为41.8 L·h^(-1)·kg^(-1)、39.9 L·h^(-1)·kg^(-1);黄芪甲苷的t_(1/2)分别为4.04 h、3.61 h,清除率(CL)分别为18.4 L·h^(-1)·kg^(-1)、19.1 L·h^(-1)·kg^(-1),同时其药时曲线下面积(AUC_((0-t)))、最大血药浓度(C_(max))、平均滞留时间(MRT_((0-t)))和表观分布容积(V_(d))差异均不大。与对照组相比,其余组在脏器湿重、脏体系数和脏器形态上无明显改变。结论大鼠单次给药后,柴胡皂苷D吸收快、消除快;黄芪甲苷吸收快,消除较慢。多次给药后,大鼠体内没有柴胡皂苷D和黄芪甲苷蓄积,与单次给药相比,主要药代动力学参数没有发生显著改变。同时柴苓舒肝丸具有低脏器毒性的优点。

Objective To investigate the in vivo pharmacokinetic characteristics and organ toxicity of Chailing Shugan Pills(formerly Chailing Qinggan Pills).Methods A total of sixty rats were randomly divided into a control group,a model group,a positive drug group and a traditional Chinese medicine group.The control group was fed normally,while a rat model of depression was established in the other groups.On this basis,the positive drug group and the traditional Chinese medicine group were respectively given fluoxetine and Chailing Shugan Pills suspension by gavage,both for 6 consecutive months.Blood samples were collected from the subclavian jugular vein of the rats in the traditional Chinese medicine group at a predetermined time while they were awake and the changes of the main components saikosaponin D and astragaloside IV were measured by the UPLC-MS/MS method to work out the pharmacokinetic characteristics after a single administration and multiple administrations.After 6 months of intragastric administrations,the remaining rats were sacrificed,the main tissues and organs were dissected,and the organ indexes were calculated by precise weighing.At the same time,hematoxylin-eosin staining(HE)was used to observe the pathological changes of each tissue and organ.Results After a single administration and multiple administrations,the half-life(t_(1/2))of saikosaponin D were 2.07 h and 2.27 h,respectively,and the clearance rate(Cl)were 41.8 L·h^(-1)·kg^(-1)and 39.9 L·h^(-1)·kg^(-1),respectively.The t_(1/2)of astragaloside IV were 4.04 h and 3.61 h,and its clearance rates(CL)were 18.4 L·h^(-1)·kg^(-1)and 19.1 L·h^(-1)·kg^(-1),respectively.At the same time,the area under the drug-time curve(AUC_((0-t))),the_(max)imum blood concentration(C_(max)),the mean retention time(MRT_((0-t)))and apparent volume of distribution(V_(d))were not significantly different.Compared with the control group,the other groups had no significant changes in the wet weight of organs,the number of organs and the morphology of organs.Conclusion After a single administration to rats,saikosaponin D is rapidly absorbed and eliminated,while astragaloside IV is rapidly absorbed yet eliminated slowly.After multiple administrations,there is no accumulation of saikosaponin D and astragaloside IV in rats,and the main pharmacokinetic parameters do not change significantly compared with the single administration.At the same time,Chailing Shugan Pills has the advantage of low organ toxicity.