詹淑玉;邵青;李正;王毅;范骁辉;

• 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。

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

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;

Email:

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.