淫羊藿低糖苷组分安全性评价及其5种主要成分的药代动力学研究  

Study on the Safety of the Low Glucoside Composites from Epimedii Folium and Pharmacokinetics of Its Five Low Glucosides

作　　者：林婷婷 李小翠[1] 邱华伟 刘中秋 朱丽君 LIN Tingting;LI Xiaocui;QIU Huawei;LIU Zhongqiu;ZHU Lijun(Guangdong Provincia Key Laboratory of Translational Cancer Research of Chinese Medicines,Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines,International Institute for Translational Chinese Medicine,School of Pharmaceutical Sciences,Guangzhou University of Chinese Medicine,Guangzhou 510006 Guangdong,China)

机构地区：[1]广州中医药大学,中药学院国际中医药转化医学研究所,教育部中医药防治肿瘤转化医学研究国际合作联合实验室,广东省中医药防治肿瘤转化药学研究重点实验室,广东广州510006

出　　处：《中药新药与临床药理》2024年第3期402-410,共9页Traditional Chinese Drug Research and Clinical Pharmacology

基　　金：国家科技重大专项课题(2017ZX09301051);国家自然科学基金国际(地区)合作研究项目(81961128028);广东省自然科学基金杰出青年项目(2022B1515020079);广州中医药大学“双一流”与高水平大学学科协同创新团队项目(2021xk77);广东省“岭南中医药”现代化基金项目(2020B1111100004);2020年广东省科技创新战略专项资金(粤港澳联合实验室)项目(2020B1212030006)。

摘　　要：目的评价淫羊藿低糖苷组分的安全性并研究其中5种低糖苷成分的药代动力学。方法4组KM小鼠分别灌胃玉米油溶媒以及1968、2625、3500 mg·kg^(-1)淫羊藿低糖苷组分后,连续7 d观察小鼠的毒性反应和死亡情况,观察结束后解剖。计算各组小鼠的脏体比和脏脑比,ELISA法测定血浆中谷丙转氨酶(ALT)和谷草转氨酶(AST)的含量,苏木精-伊红(HE)染色法观察小鼠肝脏病理变化。C57BL/6J小鼠分别尾静脉注射或灌胃宝藿苷Ⅰ、宝藿苷Ⅱ、箭藿苷A、箭藿苷B和箭藿苷C后于不同时间点采血,超高效液相色谱-串联质谱(UHPLC-MS/MS)法测定5种低糖苷的血药浓度并计算药动学参数。结果与空白对照组相比,小鼠灌胃不同剂量淫羊藿低糖苷组分后体质量、脏体比、脏脑比及血浆中ALT和AST含量均无显著性差异,肝脏病理切片也无显著变化。静脉注射后,5种低糖苷的药时曲线下面积(AUC_(0-t))分别为4.82、82.54、276.64、88.77、178.02 min·μg·mL^(-1),半衰期(t1/2)分别为60.42、115.27、67.63、131.61、129.87 min。灌胃后,5种低糖苷的AUC_(0-t)分别为31.64、18.59、3.48、2.41、2.42 min·μg·mL^(-1),峰浓度(Cmax)分别为147.23、86.76、15.58、24.34、26.12 ng·mL^(-1),达峰时间(tmax)分别为21.00、78.00、78.00、30.00、28.00 min。宝藿苷Ⅰ、宝藿苷Ⅱ、箭藿苷A、箭藿苷B、箭藿苷C口服生物利用度分别为1.91%、0.51%、0.05%、0.06%、0.04%。结论淫羊藿低糖苷组分安全性高,在3500 mg·kg^(-1)剂量下仍没有观察到肝毒性,其中5种低糖苷成分在小鼠体内吸收快、消除快,生物利用度低。Objective To evaluate the safety of the low glucoside composites of Epimedii Folium and clarify the pharmacokinetic characteristics of its five low glucosides.Methods Four groups of KM mice were orally administrated of corn oil,1968,2625 and 3500 mg·kg^(-1)low glucoside composites of Epimedii Folium,respectively.Then,the living conditions,toxic symptoms,and death of the mice were observed for 7 consecutive days.After the mice were dissected,the viscera/body ratio and the viscera/brain ratio were calculated.Besides,the contents of alanine aminotransferase(ALT)and aspartate transaminase(AST)in plasma were determined by ELISA,and the pathological changes of the liver were observed by HE staining.C57BL/6J mice were intravenously or orally administered of baohuoside I,baohuoside II,sagittatoside A,sagittatoside B and sagittatoside C.Then,blood samples were collected at different time points.The plasma concentrations of the five low glucosides were measured by UHPLC-MS/MS.Results When compared with the control group,no significant differences were found in the body mass,viscera/body ratio,viscera/brain ratio,contents of ALT and AST in plasma after oral administration of different doses of low glucoside composites to mice.Moreover,no pathological changes or damages were found in the liver sections.After intravenous injection,the AUC_(0-t)values of baohuosideⅠ,baohuosideⅡ,sagittatoside A,sagittatoside B and sagittatoside C in mice were 4.82,82.54,276.64,88.77 and 178.02 min·μg·mL^(-1),respectively.Meanwhile,the t1/2 values were 60.42,115.27,67.63,131.61 and 129.87 min,respectively.After oral administration,the AUC_(0-t)values of the five low glucosides were 31.64,18.59,3.48,2.41 and 2.42 min·μg·mL^(-1),respectively.The Cmax values were 147.23,86.76,15.58,24.34 and 26.12 ng·mL^(-1),respectively.The tmax values were 21.00,78.00,78.00,30.00 and 28.00 min,respectively.The bioavailability of baohuosideⅠ,baohuosideⅡ,sagittatoside A sagittatoside B and sagittatoside C were 1.91%,0.51%,0.05%,0.06%and 0.04%,respec

关 键 词：淫羊藿低糖苷 药代动力学 口服生物利用度 安全性 小鼠 

分 类 号：R285.5[医药卫生—中药学]