戊己丸单次与多次给药对肠易激综合征大鼠体内药代动力学行为的影响  

Comparison of pharmacokinetics after single and multiple oral administrations of Wuji Wan in irritable bowel syndrome rats

作　　者：杨紫玉 巩仔鹏[2] 王娅杰[1] 董宇[3] 董李晋川 陈颖[1] 杨庆[1] 蔡维艳[1] 李琦[1] 翁小刚[1] 郭雨轩 朱晓新[1] YANG Ziyu;GONG Zipeng;WANG Yajie;DONG Yu;DONG Lijinchuan;CHEN Ying;YANG Qing;CAI Weiyan;LI Qi;WENG Xiaogang;GUO Yuxuan;ZHU Xiaoxin(Institute of Chinese Materia Medioa,China Academy of Chinese Medical Sciences,Beijing 100700,China;Provincial Key Laboratoiy of Phannaoeutios in Guizhou Province,State Key Laboratoiy of Functions and Applications of Medicinal Plants,Engineering Research Center for Development and Application of Ethnic Medicine and Traditional Chinese Medicine,Ministiy of Education,School of Phannaoeutioal Sciences,Guizhou Medical University,Guiyang 550004;Guang'anmen Hospital,China Academy of Chinese Medical Sciences,Beijing 100053)

机构地区：[1]中国中医科学院中药研究所,北京100700 [2]贵州医科大学贵州省药物制剂重点实验室民族药与中药开发应用教育部工程研究中心药学院,贵阳550004 [3]中国中医科学院广安门医院,北京100053

出　　处：《中国比较医学杂志》2022年第1期13-23,共11页Chinese Journal of Comparative Medicine

基　　金：中国中医科学院科技创新工程项目(CI2021A04905);国家自然科学基金项目(82074103);国家“载人航天工程航天医学实验领域项目”(HYZHXM05003)。

摘　　要：目的测定戊己丸中10个活性成分单次给药和多次口服给药后不同时间点的血药浓度,比较其在正常大鼠和慢性内脏高敏感肠易激综合征(CVH-IBS)大鼠体内药代动力学特征的差异。方法采用乳鼠结肠球囊刺激法制备CVH-IBS大鼠模型,并对其进行内脏敏感性评价。单次或多次灌胃给予戊己丸提取物后于不同时间点从颈静脉采血,采用超高效液相色谱-串联质谱(UPLC-MS/MS)同时检测血浆中10个戊己丸活性成分的血药浓度,比较其药代动力学参数的差异。结果CVH-IBS大鼠内脏敏感性增强。与单次给药相比,多次给药正常与模型大鼠达峰时间(t_(max))均提前。单次给药后模型与正常大鼠的差异可正向验证前期实验结果。多次给药后与正常大鼠相比,模型大鼠体内戊己丸活性成分血药浓度峰值(C_(max))、曲线下面积(AUC_(0-t))、总清除率(Cl)发生显著改变。盐酸小檗碱、盐酸黄连碱、表小檗碱C_(max)显著升高,盐酸巴马汀、盐酸药根碱、二氢小檗碱、吴茱萸碱、吴茱萸内酯C_(max)显著下降;盐酸黄连碱、表小檗碱AUC_(0-t)显著升高,盐酸巴马汀、二氢小檗碱、盐酸药根碱、吴茱萸碱、吴茱萸内酯AUC_(0-t)显著下降;盐酸黄连碱、吴茱萸内酯Cl明显升高,表小檗碱Cl显著降低。盐酸巴马汀、芍药内酯苷t_(1/2)明显降低;盐酸药根碱V_(d)显著升高。模型大鼠多次给药和单次给药相比较,黄连活性成分盐酸小檗碱、盐酸药根碱、表小檗碱、二氢小檗碱C_(max)明显降低;盐酸药根碱Cl明显降低。白芍活性成分芍药苷t_(1/2)明显下降,Cl明显上升。结论戊己丸中活性成分在正常大鼠、CVH-IBS大鼠、戊己丸治疗后期的CVH-IBS大鼠体内的药代动力学行为存在明显差异,这可能与IBS治疗早期肠道屏障被破坏和治疗后期肠道屏障修复、药物肝肠循环蓄积作用以及肝酶的活性等代谢功能改变相关。Objective The plasma concentrations of 10 active components in Wuji Wan were measured at various time points after single and multiple oral administrations to compare its pharmacokinetic characteristics in normal rats and rats with chronic visceral hypersensitivity irritable bowel syndrome(CVH-IBS)in different courses.Methods The CVH-IBS rat model was established by the neonatal rat colon balloon stimulation method and visceral sensitivity was evaluated.After single or multiple intragastric administrations of Wuji Wan,blood was collected from the jugular vein at various time points.Ultra-performance liquid chromatography-MS/MS was used to simultaneously measure the plasma concentrations of 10 active components of Wuji Wan in plasma and compare differences in pharmacokinetic parameters.Results Visceral sensitivity was enhanced in CVH-IBS rats.Compared with a single dose,the peak time(t_(max))of multiple doses in normal and model rats was earlier.The difference between model and normal rats after a single dose verified the previous experimental results.Compared with normal rats,the active component C_(max),AUC_(0-t)and Cl of Wuji Wan in model rats were changed significantly after multiple administrations.The C_(max)of berberine hydrochloride,coptisine hydrochloride and epiberberine was increased significantly,while that of palmatine hydrochloride,jatrorrhizine hydrochloride,dihydroberberine,evodiamine and evodia lactone was decreased significantly.Epiberberine C_(max)was decreased significantly.Coptisine hydrochloride and epiberberine AUC_(0-t)was increased significantly.Palmatine hydrochloride,dihydroberberine,jatrorrhizine hydrochloride,evodiamine and evodia lactone AUC_(0-t)was decreased significantly.Coptisine hydrochloride and evodia lactone Cl was increased significantly.Epiberberine Cl was reduced significantly.Palmatine hydrochloride and albiflorin t_(1/2)was reduced significantly.Jatrorrhizine hydrochloride V_(d)was increased significantly.By comparing multiple and single administrations in model rats,the

关 键 词：戊己丸 肠易激综合征(IBS) 乳鼠结肠球囊刺激法 药代动力学 

分 类 号：R-33[医药卫生]