地黄叶总苷胶囊在幼龄大鼠体内毒代动力学研究  

Toxokinetics Study of Rehmannia glutinosa Leaf Total Glycosides Capsules in Young Rats

作　　者：叶潇 郑爽 张佳宁 于敏[1] 黄舒佳 王宇 肖华 刘艳华 刘颖[1] YE Xiao;ZHENG Shuang;ZHANG Jianing;YU Min;HUANG Shujia;WANG Yu;XIAO Hua;LIU Yanhua;LIU Ying(Beijing Key Laboratory for Safety Evaluation of Drugs,Institute for Safety Evaluation,National Institutes for Food and Drug Control,Beijing 100176,China;Sichuan Medco Pharmaceutical Stock Co.,Ltd.,Shifang 618400,China)

机构地区：[1]中国食品药品检定研究院安全评价研究所,药物非临床安全评价研究北京市重点实验室,北京100176 [2]四川美大康药业股份有限公司,什邡四川618400

出　　处：《中国药学杂志》2025年第6期612-619,共8页Chinese Pharmaceutical Journal

摘　　要：目的 建立测定幼龄大鼠血浆中毛蕊花糖苷(地黄叶总苷胶囊主要成分)浓度的液相色谱-串联质谱联用(liquid chromatography-tandem mass spectrometry, LC-MS/MS)检测方法,研究毛蕊花糖苷在幼龄Wistar大鼠重复灌胃给予不同剂量水平的地黄叶总苷胶囊后体内的暴露程度及毒代动力学特征。方法 血浆样品采用甲醇-乙腈(1∶1)进行蛋白沉淀处理,液相分离采用Waters ACQUITY UPLC HSS T3色谱柱(2.1 mm×100 mm, 1.7μm),以含体积分数0.1%甲酸水溶液-0.1%甲酸乙腈溶液为流动相进行,流速为0.5 mL·min^(-1),进样量为2μL;质谱检测采用电喷雾负离子(ESI-)模式和多重反应监测(MRM)扫描方式,毛蕊花糖苷监测离子对623.1/160.9,染料木素监测离子对269.0/158.9,用作内标;通过建立的LC-MS/MS法分析测定地黄叶胶囊重复给药幼龄Wistar大鼠毒性试验首、末次后大鼠血浆中毛蕊花糖苷的药物浓度,绘制药-时曲线并计算动力学参数。结果 建立了基于LC-MS/MS法测定大鼠血浆中毛蕊花糖苷含量的方法并进行了方法学验证,该方法可在2~500 ng·mL^(-1)内准确测定毛蕊花糖苷含量。幼龄Wistar大鼠重复灌胃给予地黄叶总苷胶囊内容物混悬液8周,在30~750 mg·kg^(-1)内,体内毛蕊花糖苷的暴露量无蓄积现象;体内暴露量与所给予的剂量不呈线性动力学特征趋势。结论 本研究应用LC-MS/MS技术建立的方法可用于大鼠血浆中地黄叶总苷胶囊中毛蕊花糖苷浓度的测定,并支持完成了地黄叶总苷胶囊在幼龄大鼠体内的毒代动力学研究。OBJECTIVE To establish an LC-MS/MS method for determining the concentration of acteoside(the main component of Rehmannia glutinosa leaf total glycosides capsules)in the plasma of young rats and investigate the exposure levels and toxicokinetic characteristics of acteoside following repeated oral gavage administration of different doses of Rehmannia glutinosa leaf total glycosides capsules.METHODS Plasma samples were processed using protein precipitation with methanol-acetonitrile(1∶1).Chromatographic separation was performed on a Waters ACQUITY UPLC HSS T3 column(2.1 mm×100 mm,1.7μm),with mobile phase consisting of 0.1%formic acid in water and 0.1%formic acid in acetonitrile,at a flow rate of 0.5 mL·min^(-1).The injection volume was 2μL.Mass spectrometry detection was carried out using electrospray ionization in negative mode(ESI-1)and multiple reaction monitoring(MRM).The ion transitions monitored were 623.1/160.9 for acteoside and 269.0/158.9 for genistein which served as the internal standard.The established LC-MS/MS method was applied to analyze the plasma concentrations of acteoside in young Wistar rats after the first and last administrations of Rehmannia glutinosa leaf total glycosides capsules during a toxicity study.Pharmacokinetic profiles were constructed and kinetic parameters were calculated.RESULTS An LC-MS/MS method was developed and validated for the accurate determination of acteoside in rat plasma within a concentration range of 2-500 ng·mL^(-1).Young Wistar rats were repeatedly gavaged with suspensions of Rehmannia glutinosa leaf total glycosides capsules for 8 weeks at dose levels ranging from 30 to 750 mg·kg^(-1).No accumulation of acteoside exposure was observed within this dose range,and the exposure did not exhibit linear kinetics with increasing dose.CONCLUSION The developed LC-MS/MS method is applicable for measuring the concentration of acteoside from Rehmannia glutinosa leaf total glycosides capsules in rat plasma and supports toxicokinetic studies in young rats.

关 键 词：地黄叶总苷胶囊 毛蕊花糖苷 液相色谱-串联质谱联用 毒代动力学 

分 类 号：R966[医药卫生—药理学]