詹淑玉;邵青;李正;王毅;范骁辉;
ZHAN Shu-yu;SHAO Qing;LI Zheng;WANG Yi;FAN Xiao-hui;Department of Traditional Chinese Medicine Science and Engineering,College of Pharmaceutical Sciences,Zhejiang University;State Key Laboratory of Modern Chinese Medicine,Tianjin University of TraditionalChinese Medicine;

• 1:浙江大学药学院中药科学与工程学系
• 2:天津中医药大学中医药研究院

摘要(Abstract)：

该文研究生脉注射液中主要成分人参皂苷Rg1和Rb1在心肌缺血大鼠体内的药动学过程及其诱导体内NO释放效应的药动学-药效学(PK-PD)结合模型。以大鼠皮下注射异丙肾上腺素(ISO)制备心肌缺血模型。模型大鼠静脉给予生脉注射液(10.8 mL·kg-1),于给药后不同时间点采集大鼠血清,测定血清中人参皂苷Rg1和Rb1的浓度,绘制药-时曲线,拟合药动学模型,计算药动学参数;同时测定血清中NO代谢产物NO2-和NO3-水平,绘制时-效曲线,采用Sheiner等提出的效应室理论建立PK-PD结合模型,计算药效学参数。研究结果显示人参皂苷Rg1和Rb1在大鼠体内的药动学过程均符合二房室开放模型,人参皂苷Rg1在体内表现出快消除的特点,人参皂苷Rb1表现出慢消除的特点。生脉注射液诱导大鼠体内NO释放效应与人参皂苷Rg1和Rb1的血药浓度不直接相关,效应滞后于血药浓度,效应与人参皂苷Rg1和Rb1的效应室浓度成良好的相关性,符合Sigmoid-Emax模型。该研究成功建立了生脉注射液在心肌缺血大鼠体内的PK-PD结合模型,可较有效地用于预测生脉注射液的血药浓度和效应。
It is the objective of this paper to study pharmacokinetics-pharmacodynamics( PK-PD) characteristics of ginsenoside Rg1and Rb1on the effect of inducing nitric oxide( NO) release after intravenous administration of Shengmai injection to rats with myocardial ischemia. The model of myocardial ischemia rats was produced by subcutaneous injection of isoproterenol. The serum samples were collected at different time points after intravenous administration of Shengmai injection to rats with the dose of 10. 8 mL·kg-1. The concentrations of ginsenoside Rg1and Rb1in serum were determined,and then the concentration-time curves were drawn. Pharmacokinetic parameters of ginsenoside Rg1and Rb1were calculated after the construction of pharmacokinetic models. Meanwhile,NO2-and NO3-,the metabolites of NO,in serum were determined,and then the effect-time curve was drawn. The combined PK-PD model was established based on the theory of effect compartment by Sheiner et al. Then pharmacodynamic parameters were calculated. The results indicated that the pharmacokinetics of ginsenoside Rg1and Rb1conformed to a two-compartment model. Ginsenoside Rg1and Rb1 exhibited quick and slow elimination in rats respectively. The effect of Shengmai injection on inducing NO release did not relate directly with and lagged behind the concentrations of ginsenoside Rg1and Rb1in serum. The effect exhibited good correlation with ginsenoside Rg1and Rb1levels in effect compartment. The relationship between effect and serum concentration fits Sigmoid-Emaxmodel. This study successfully established the combined PK-PD model of ginsenoside Rg1and Rb1after intravenous administration of Shengmai injection to rats. The model can efficiently predict the concentration and effect of Shengmai injection in vivo.

关键词(KeyWords)： 生脉注射液;人参皂苷Rg1;人参皂苷Rb1;一氧化氮;药动学-药效学结合
Shengmai injection;ginsenoside Rg1;ginsenoside Rb1;nitric oxide;the combined pharmacokinetics-pharmacodynamics(PK-PD)

Abstract:

Keywords:

基金项目(Foundation): 国家“重大新药创制”科技重大专项(2009ZX09502-005);; 国家自然科学基金项目(81173467)

作者(Author): 詹淑玉;邵青;李正;王毅;范骁辉;
ZHAN Shu-yu;SHAO Qing;LI Zheng;WANG Yi;FAN Xiao-hui;Department of Traditional Chinese Medicine Science and Engineering,College of Pharmaceutical Sciences,Zhejiang University;State Key Laboratory of Modern Chinese Medicine,Tianjin University of TraditionalChinese Medicine;

Email:

DOI:

参考文献(References)：

• [1]Abdel-Rahman S M,Kauffman R E.The integration of pharmacokinetics and pharmacodynamics:understanding dose-response[J].Annu Rev Pharmacol Toxicol,2004,44:111.
• [2]Csajka C,Verotta D.Pharmacokinetic-pharmacodynamic modelling:history and perspectives[J].J Pharmacokinet Pharmacodyn,2006,33(3):227.
• [3]袁美燕,吴虹.PK-PD模型在中药药物代谢动力学中的应用[J].安徽中医学院学报,2009,28(5):86.
• [4]曹岗,张云,丛晓东,等.PK-PD模型在中药药动学中的应用[J].中草药,2009,40(11):1830.
• [5]陈琼,冬雪川,师少军,等.蝙蝠葛苏林碱和蝙蝠葛碱犬体内药动学-药效学结合研究[J].中国药学杂志,2004,39(5):366.
• [6]Chen J,Yao Y,Chen H,et al.Shengmai(a traditional Chinese herbal medicine)for heart failure[J].Cochrane Database Syst Rev,2012,11:CD005052.
• [7]石蓓佳,吴莉.生脉注射液在家兔体内的药代动力学研究[J].中成药,2009,31(4):653.
• [8]李国信,唐思,夏素霞,等.生脉拆方系列注射液中人参皂苷Rg1和Re药代动力学研究[J].中华中医药学刊,2010,28(11):2310.
• [9]姜春梅,李国信,夏素霞,等.生脉注射液中人参皂苷Rb1在健康人体的药动学[J].中国新药杂志,2011,20(9):803.
• [10]Sheiner L B,Stanski D R,Vozeh S,et al.Simultaneous modeling of pharmacokinetics and pharmacodynamics:application to d-tubocurarine[J].Clin Pharmacol Ther,1979,25(3):358.
• [11]Holford N H,Sheiner L B.Understanding the dose-effect relationship:clinical application of pharmacokinetic-pharmacodynamic models[J].Clin Pharmacokinet,1981,6(6):429.
• [12]郭文婧.生脉方药代动力学研究[D].杭州:浙江大学,2012.
• [13]Zhan S Y,Shao Q,Liu L,et al.A simple and accurate method to determine nitrite and nitrate in serum based on high-performance liquid chromatography with fluorescence detection[J].Biomed Chromatogr,2013,27(11):1547.
• [14]Xu Q F,Fang X L,Chen D F.Pharmacokinetics and bioavailability of ginsenoside Rb1and Rg1from Panax notoginseng in rats[J].J Ethnopharmacol,2003,84(2/3):187.
• [15]Han M,Fu S,Fang X L.Comparison between the characteristics of absorption and pharmacokinetic behavior of ginsenoside Rg1and ginsenoside Rb,of Panax notoginseng saponins[J].Acta Pharm Sin,2007,42(8):849.
• [16]Liu H,Yang J,Du F,et al.Absorption and disposition of ginsenosides after oral administration of Panax notoginseng extract to rats[J].Drug Metab Dispos,2009,37(12):2290.
• [17]Sheiner L B,Steimer J L.Pharmacokinetic/pharmacodynamic modeling in drug development[J].Annu Rev Pharmacol Toxicol,2000,40:67.
• [18]Derendorf H,Lesko L J,Chaikin P,et al.Pharmacokinetic/pharmacodynamic modeling in drug research and development[J].J Clin Pharmacol,2000,40(12 Pt 2):1399.
• [19]Leung K W,Cheng Y K,Mak N K,et al.Signaling pathway of ginsenoside-Rg1leading to nitric oxide production in endothelial cells[J].FEBS Lett,2006,580(13):3211.
• [20]Yu J,Eto M,Akishita M,et al.Signaling pathway of nitric oxide production induced by ginsenoside Rb1in human aortic endothelial cells:a possible involvement of androgen receptor[J].Biochem Biophysi Res Communic,2007,353(3):764.
• [21]Leung K W,Leung F P,Mak N K,et al.Protopanaxadiol and protopanaxatriol bind to glucocorticoid and oestrogen receptors in endothelial cells[J].Br J Pharmacol,2009,156(4):626.
• [22]Pan C,Huo Y,An X,et al.Panax notoginseng and its components decreased hypertension via stimulation of endothelial-dependent vessel dilatation[J].Vascul Pharmacol,2012,56(3/4):150.
• [23]Chu K M,Hu O Y,Shieh S M.Cardiovascular effect and simultaneous pharmacokinetic and pharmacodynamic modeling of pimobendan in healthy normal subjects[J].Drug Metab Dispos,1999,27(6):701.
• [24]Liu X Y,Wang B J,Yuan G Y,et al.Comparison of different pharmacodynamic models for pharmacokinetic-pharmacodynamic(PK-PD)modeling of carvedilol[J].Acta Pharm Sin,2009,44(4):406.
• [25]师少军,顾世芬,陈汇,等.蝙蝠葛碱在犬体内的药代动力学和药效动力学研究[J].中国药理学通报,2005,21(4):464.