酸枣仁化学成分体内过程及其质量标志物研究思路探讨
|
摘要
酸枣仁是公认的大宗中药品种之一,具有养心安神、补肝、敛汗生津之功效,是中医治疗失眠的首选药物。目前,酸枣仁化学成分研究较为清晰,其主要化学成分为黄酮类、皂苷类、生物碱类和三萜酸类等,结构丰富多样。酸枣仁化学成分的多样性决定了其生物学活性和药理作用的多样性,同时导致其药动学复杂的特性。通过对国内外文献分析与总结,梳理了酸枣仁化学成分(黄酮类、皂苷类)的药动学参数、吸收情况、组织分布特征和代谢研究成果(肠道菌群代谢转化、肝微粒体代谢转化、体内代谢转化),以期从体内过程的角度进行深度发掘和分析,为酸枣仁药效物质发现提供新的研究方向,同时为酸枣仁质量标志物的筛选和确定提供参考。
Ziziphi Spinosae Semen(ZSS),one of the major traditional Chinese medicine varieties,has been used as a sedative medicine in China for thousands of years.The classical application of ZSS is nourishing heart and tranquilizing mind,tonifying the liver,arresting the sweat and promoting the production of the body fluid.Up to now,extensive chemical studies have also been conducted,suggesting the presence of alkaloids,flavonoids,saponins,and triterpene acids.Given the chemical diversity of ZSS,it is generally considered that the biological activity and pharmacological effect were accomplished by an array of phytochemicals.Due to complicated chemical composition of ZSS,compounds can be absorbed into circulation and then converted into even more metabolites.This review summarizes the recent advances in pharmacokinetics,absorption,and distribution,as well as biotransformation and/or metabolism of chemical compounds from ZSS,which might greatly contribute to supply the research target and scientific basis in clarifying the effective substance basis and the quality marker(Q-marker) of ZSS.
Ziziphi Spinosae Semen(ZSS),one of the major traditional Chinese medicine varieties,has been used as a sedative medicine in China for thousands of years.The classical application of ZSS is nourishing heart and tranquilizing mind,tonifying the liver,arresting the sweat and promoting the production of the body fluid.Up to now,extensive chemical studies have also been conducted,suggesting the presence of alkaloids,flavonoids,saponins,and triterpene acids.Given the chemical diversity of ZSS,it is generally considered that the biological activity and pharmacological effect were accomplished by an array of phytochemicals.Due to complicated chemical composition of ZSS,compounds can be absorbed into circulation and then converted into even more metabolites.This review summarizes the recent advances in pharmacokinetics,absorption,and distribution,as well as biotransformation and/or metabolism of chemical compounds from ZSS,which might greatly contribute to supply the research target and scientific basis in clarifying the effective substance basis and the quality marker(Q-marker) of ZSS.
引文
[1]中国药典[S].一部.2015.
[2]You Z L,Xia Q,Liang F R,et al.Effects on the expression of GABAA receptor subunits by jujuboside Atreatment in rat hippocampal neurons[J].JEthnopharmacol,2010,128(2):419-423.
[3]Liu J,Zhai W M,Yang Y X,et al.GABA and 5-HTsystems are implicated in the anxiolytic-like effect of spinosin in mice[J].Pharmacol Biochem Be,2015,128:41-49.
[4]Xie J B,Zhang Y Q,Wang L J,et al.Composition of fatty oils from Semen Ziziphi Spinosae and its cardiotonic effect on isolated toad hearts[J].Nat Prod Res,2012,26(5):479-483.
[5]Alreza S M,Bajpai V K,Kang S C.Antioxidant and antilisterial effect of seed essential oil and organic extracts from Zizyphus jujuba[J].Food Chem Toxicol,2009,47(9):2374-2380.
[6]叶琳.酸枣仁效用与临床应用分析[J].上海中医药杂志,2014,48(7):74-75.
[7]朱红霞,胡学军.中药治疗失眠的现代用药规律研究[J].中华中医药学刊,2008,26(4):775-776.
[8]马进杰,刘萍,马百平.酸枣仁化学成分及其镇静催眠作用研究进展[J].国际药学研究杂志,2011,38(3):206-211.
[9]耿欣,李廷利.酸枣仁主要化学成分及药理作用研究进展[J].中医药学报,2016,44(5):84-86.
[10]Kim J H.Chemical compounds in the seeds of Ziziphus jujuba var.spinosa[J].Koren Herb Med Inf,2016,4(1):13-28.
[11]宋伟,唐生安,曹冰雁,等.酸枣仁黄酮部位不同配伍的解郁安神作用及谱-效相关性分析[J].中草药,2018,49(5):1123-1131.
[12]Li Y J,Liang X M,Xiao H B,et al.Pharmacokinetic study on spinosin in rat plasma after oral administration of Suanzaoren extract at a single dose[J].Acta Pharm Sin,2003,38(6):448-450.
[13]Li Y J,Dai Y H,Yu Y L,et al.Pharmacokinetics and tissue distribution of spinosin after intravenous administration in rats[J].Yakugaku Zasshi,2007,127(8):1231-1235.
[14]Li Y J,Yao M,Cheng S.Quantitative determination of spinosin in rat plasma by liquid chromatography-tandem mass spectrometry method[J].J Pharmaceut Biomed,2008,48(4):1169-1173.
[15]鲍康德,赵继红,齐炼文.SPE-HPLC-DAD同时测定大鼠血浆中斯皮诺素和6′′′-阿魏酰斯皮诺素的含量[J].中国现代应用药学,2013,30(7):707-711.
[16]Qiao L D,Liu Y,Chen X Y,et al.A HPLC-MS/MSmethod for determination of 6′′′-feruloylspinosin in rat plasma and tissues:Pharmacokinetics and tissue distribution study[J].J Pharmaceut Biomed,2016,121:77-83.
[17]Zhao X T,Liu J J,Wen Z Y,et al.The pharmacokinetics and tissue distribution of coumaroylspinosin in rat:a novel flavone C-glycoside derived from Zizyphi Spinosi Semen[J].J Chromatogr B,2017,1046:18-25.
[18]Ma R H,Yang J,Qi L W,et al.In vivo microdialysis with LC-MS for analysis of spinosin and its interaction with cyclosporin A in rat brain,blood and bile[J].JPharmaceut Biomed,2012,61(5):22-29.
[19]王超.酸枣仁中有效成分的提取及在大鼠体内的吸收研究[D].天津:天津商业大学,2011.
[20]Liu C H,Li Y Y,Zhong Y H,et al.An LC-MS/MSmethod for determination of jujuboside A in rat plasma and its application to pharmacokinetic studies[J].JChromatogr B,2012,899(7):21-26.
[21]Zheng X Y,Yang X X,Le Q Y,et al.Development and validation of an UPLC-MS/MS method for determination of jujuboside B in rat plasma and its application in pharmacokinetic and bioavailability studies[J].Anal Methods,2015,7(10):4049-4054.
[22]Chen C Y,Chen Y F,Wu C H.What is the effective component in Suanzaoren Decoction for curing insomnia?Discovery by virtual screening and molecular dynamic simulation[J].J Biomol Struct Dyn,2008,26(1):57-64.
[23]Chen Y C.Chemoinformatics and pharmacoinformatics approach for exploring the GABA-A agonist from Chinese herb Suanzaoren[J].J Taiwan Inst Chem E,2009,40(1):36-47.
[24]张妍,解军波,张彦青.HPLC-MS/MS法测定大鼠血浆中酸枣仁皂苷A含量及其药动学研究[J].食品研究与开发,2015,36(3):110-114.
[25]章新晶.酸枣仁皂苷A生物吸收的细胞学机制[D].南昌:南昌大学,2006.
[26]张婷,解军波,刘子艳,等.斯皮诺素在体胃肠吸收动力学研究[J].中国实验方剂学杂志,2012,18(13):134-139.
[27]Zhang Y Q,Zhang T,Wang F L,et al.Brain tissue distribution of spinosin in rats determined by a new high-performance liquid chromatography-electrospray ionization-mass/mass spectrometry method[J].JChromatogr Sci,2015,53(1):1-7.
[28]Zhang Y Q,Ma G J,Xie J B.Tissue distribution of jujuboside A in Sprague-Dawley rats determined by an efficient HPLC-ESI-MS/MS method[J].J Liq Chromatogr R T,2015,38(2):215-221.
[29]崔瑛,杨晶晶,郭敏娟,等.基于“病证-效应-生物样本分析”方法的酸枣仁“安神”药性物质及归经的研究[J].世界科学技术-中医药现代化,2015,17(3):569-577.
[30]郭敏娟.酸枣仁对阴虚大鼠焦虑行为的影响及指标成分体内分布观察[D].郑州:河南中医学院,2014.
[31]Li H K,Zhou M M,Zhao A H,et al.Traditional Chinese medicine:Balancing the gut ecosystem[J].Phytother Res,2009,23(9):1332-1335.
[32]Ridaura V,Belkaid Y.Gut microbiota:The link to your second brain[J].Cell,2015,161(2):193-194.
[33]Jiang J G,Huang X J,Chen J,et al.Comparison of the sedative and hypnotic effects of flavonoids,saponins,and polysaccharides extracted from Semen Ziziphus Jujube[J].Nat Prod Res,2007,21(4):310-320.
[34]马桂劼,张妍,张明春,等.HPLC-MS/MS法研究大鼠胃内容物对酸枣仁皂苷A的体外代谢作用[J].食品研究与开发,2013,34(19):1-4.
[35]Zhang Y Q,Zhang Y,Zhang K S,et al.Degradation kinetics of jujuboside B by rat intestinal flora in vitro with an RRLC-MS-MS method[J].J Chromatogr Sci,2014,52(7):1-6.
[36]Zhang Y,Xie J B,Zhang Y Q,et al.Degradation kinetics of jujuboside A by rat intestinal flora and identification of the metabolites by HPLC-MS/MS[J].Int J F Prop,2014,17(8):1841-1849.
[37]张群.酸枣仁总皂苷的提取纯化及酸枣仁皂苷A的生物转化研究[D].济南:山东中医药大学,2016.
[38]马桂劼.酸枣仁皂苷A引起的肠道和主要脏腑之间的信息交流[D].天津:天津商业大学,2014.
[39]Zhang T,Xie J B,Zhang Y Q,et al.High performance liquid chromatography coupled with tandem mass spectrometry applied for metabolic study of spinosin by rat intestinal flora[J].J Liq Chromatogr R T,2013,36(10):1391-1400.
[40]Song P P,Zhang Y Q,Qiao L D,et al.A new HPLC-MS/MS method for investigating degradation kinetics of 6'''-feruloylspinosin and identifying its metabolites by rat intestinal bacterial flora in vitro[J].JLiq Chromatogr R T,2016,39(15):724-729.
[41]Jiao L J,Li Y X,Zhang Y Q,et al.Degradation kinetics of 6'''-p-coumaroylspinosin and identification of its metabolites by rat intestinal flora[J].J Agr Food Chem,2017,65(22):1-31.
[42]Vollmer M,Esders S,Farquharson F M,et al.Mutual interaction of phenolic compounds and microbiota:metabolism of complex phenolic apigenin C-and kaempferol O-derivatives by human fecal samples[J].JAgr Food Chem,2018,66(2):1-46.
[43]张巧月.基于液质联用技术的酸枣仁多组分分析与体外代谢研究及连翘心质量标准的建立[D].石家庄:河北医科大学,2016.
[44]Bao K D,Li P,Qi L W,et al.Characterization of flavonoid metabolites in rat plasma,urine,and feces after oral administration of Semen Ziziphi Spinosae extract by HPLC-diode-array detection(DAD)and ion-trap mass spectrometry(MS(n))[J].Chem Pharm Bull,2009,57(2):144-148.
[45]张雷,向诚,王邠,等.酸枣仁总黄酮在大鼠尿液和粪便中的代谢与排泄[J].中国中药杂志,2009,34(3):340-343.
[46]Ren Y,Wang P J,Wu C S,et al.Identification of the metabolites after oral administration of extract of Ziziphi Spinosae Semen to rats or dogs by high-performance liquid chromatography/linear ion trap FTICR hybrid mass spectrometry[J].Biomed Chromatogr,2013,27(1):17-26.
[47]李强,杜晨晖,张敏,等.血清化学与网络药理学关联研究酸枣仁的体内效应成分[J].中草药,2017,48(10):1936-1943.
[48]闫艳,李强,杜晨晖,等.基于体内-体外物质组关联分析酸枣仁潜在效应物质[J].药学学报,2017,52(2):283-290.
[49]王羽凝,穆丽华,许璐,等.基于UPLC-Q-TOF-MSE分析芍枣胶囊在大鼠体内的代谢产物[J].中国实验方剂学杂志,2016,22(20):77-81.
[50]王晶娟,刘洋,赵保胜,等.中药“质效代关联”研究方法与理论的建立[J].中草药,2014,45(11):1507-1510.
[51]刘昌孝,陈士林,肖小河,等.中药质量标志物(Q-Marker):中药产品质量控制的新概念[J].中草药,2016,47(9):1443-1457.
[52]胡明亚.酸枣仁的药理作用及现代临床应用研究[J].中医临床研究,2012,4(19):20.
[53]Zhang J W,Zhou F,Wu X L,et al.Cellular pharmacokinetic mechanisms of adriamycin resistance and its modulation by 20(S)-ginsenoside Rh2 in MCF-7/Adr cells[J].Brit J Pharmacol,2012,165(1):120-134.
[54]乔雪,果德安,叶敏.中药体内代谢研究的思路与方法[J].世界科学技术-中医药现代化,2014,16(3):532-537.
[55]Xing R,Zhou L,Xie L,et al.Development of a systematic approach to rapid classification and identification of notoginsenosides and metabolites in rat feces based on liquid chromatography coupled triple time-of-flight mass spectrometry[J].Anal Chim Acta,2015,867:56-66.
[56]刘洋,潘艳丽,王晶娟,等.多成分药物代谢理论及技术方法分析[J].中草药,2014,45(12):1663-1667.
[57]杨秀伟.基于体内过程的中药有效成分和有效效应物质的发现策略[J].中国中药杂志,2007,32(5):365-370.
[58]Xie T,Liang Y,Hao H P,et al.Rapid identification of ophiopogonins and ophiopogonones in Ophiopogon Japonicus extract with a practical technique of mass defect filtering based on high resolution mass spectrometry[J].J Chromatogr A,2012,1227(5):234-244.
[59]Xue Q,Qi W,Shuang W,et al.Compound to extract to formulation:A knowledge-transmitting approach for metabolites identification of Gegen-Qinlian Decoction,a traditional Chinese medicine formula[J].Sci Rep,2016,6:39534.
[60]Qiao X,Ye M,Xiang C,et al.Analytical strategy to reveal the in vivo process of multi-component herbal medicine:A pharmacokinetic study of licorice using liquid chromatography coupled with triple quadrupole mass spectrometry[J].J Chromatogr A,2012,1258(19):84-93.
[2]You Z L,Xia Q,Liang F R,et al.Effects on the expression of GABAA receptor subunits by jujuboside Atreatment in rat hippocampal neurons[J].JEthnopharmacol,2010,128(2):419-423.
[3]Liu J,Zhai W M,Yang Y X,et al.GABA and 5-HTsystems are implicated in the anxiolytic-like effect of spinosin in mice[J].Pharmacol Biochem Be,2015,128:41-49.
[4]Xie J B,Zhang Y Q,Wang L J,et al.Composition of fatty oils from Semen Ziziphi Spinosae and its cardiotonic effect on isolated toad hearts[J].Nat Prod Res,2012,26(5):479-483.
[5]Alreza S M,Bajpai V K,Kang S C.Antioxidant and antilisterial effect of seed essential oil and organic extracts from Zizyphus jujuba[J].Food Chem Toxicol,2009,47(9):2374-2380.
[6]叶琳.酸枣仁效用与临床应用分析[J].上海中医药杂志,2014,48(7):74-75.
[7]朱红霞,胡学军.中药治疗失眠的现代用药规律研究[J].中华中医药学刊,2008,26(4):775-776.
[8]马进杰,刘萍,马百平.酸枣仁化学成分及其镇静催眠作用研究进展[J].国际药学研究杂志,2011,38(3):206-211.
[9]耿欣,李廷利.酸枣仁主要化学成分及药理作用研究进展[J].中医药学报,2016,44(5):84-86.
[10]Kim J H.Chemical compounds in the seeds of Ziziphus jujuba var.spinosa[J].Koren Herb Med Inf,2016,4(1):13-28.
[11]宋伟,唐生安,曹冰雁,等.酸枣仁黄酮部位不同配伍的解郁安神作用及谱-效相关性分析[J].中草药,2018,49(5):1123-1131.
[12]Li Y J,Liang X M,Xiao H B,et al.Pharmacokinetic study on spinosin in rat plasma after oral administration of Suanzaoren extract at a single dose[J].Acta Pharm Sin,2003,38(6):448-450.
[13]Li Y J,Dai Y H,Yu Y L,et al.Pharmacokinetics and tissue distribution of spinosin after intravenous administration in rats[J].Yakugaku Zasshi,2007,127(8):1231-1235.
[14]Li Y J,Yao M,Cheng S.Quantitative determination of spinosin in rat plasma by liquid chromatography-tandem mass spectrometry method[J].J Pharmaceut Biomed,2008,48(4):1169-1173.
[15]鲍康德,赵继红,齐炼文.SPE-HPLC-DAD同时测定大鼠血浆中斯皮诺素和6′′′-阿魏酰斯皮诺素的含量[J].中国现代应用药学,2013,30(7):707-711.
[16]Qiao L D,Liu Y,Chen X Y,et al.A HPLC-MS/MSmethod for determination of 6′′′-feruloylspinosin in rat plasma and tissues:Pharmacokinetics and tissue distribution study[J].J Pharmaceut Biomed,2016,121:77-83.
[17]Zhao X T,Liu J J,Wen Z Y,et al.The pharmacokinetics and tissue distribution of coumaroylspinosin in rat:a novel flavone C-glycoside derived from Zizyphi Spinosi Semen[J].J Chromatogr B,2017,1046:18-25.
[18]Ma R H,Yang J,Qi L W,et al.In vivo microdialysis with LC-MS for analysis of spinosin and its interaction with cyclosporin A in rat brain,blood and bile[J].JPharmaceut Biomed,2012,61(5):22-29.
[19]王超.酸枣仁中有效成分的提取及在大鼠体内的吸收研究[D].天津:天津商业大学,2011.
[20]Liu C H,Li Y Y,Zhong Y H,et al.An LC-MS/MSmethod for determination of jujuboside A in rat plasma and its application to pharmacokinetic studies[J].JChromatogr B,2012,899(7):21-26.
[21]Zheng X Y,Yang X X,Le Q Y,et al.Development and validation of an UPLC-MS/MS method for determination of jujuboside B in rat plasma and its application in pharmacokinetic and bioavailability studies[J].Anal Methods,2015,7(10):4049-4054.
[22]Chen C Y,Chen Y F,Wu C H.What is the effective component in Suanzaoren Decoction for curing insomnia?Discovery by virtual screening and molecular dynamic simulation[J].J Biomol Struct Dyn,2008,26(1):57-64.
[23]Chen Y C.Chemoinformatics and pharmacoinformatics approach for exploring the GABA-A agonist from Chinese herb Suanzaoren[J].J Taiwan Inst Chem E,2009,40(1):36-47.
[24]张妍,解军波,张彦青.HPLC-MS/MS法测定大鼠血浆中酸枣仁皂苷A含量及其药动学研究[J].食品研究与开发,2015,36(3):110-114.
[25]章新晶.酸枣仁皂苷A生物吸收的细胞学机制[D].南昌:南昌大学,2006.
[26]张婷,解军波,刘子艳,等.斯皮诺素在体胃肠吸收动力学研究[J].中国实验方剂学杂志,2012,18(13):134-139.
[27]Zhang Y Q,Zhang T,Wang F L,et al.Brain tissue distribution of spinosin in rats determined by a new high-performance liquid chromatography-electrospray ionization-mass/mass spectrometry method[J].JChromatogr Sci,2015,53(1):1-7.
[28]Zhang Y Q,Ma G J,Xie J B.Tissue distribution of jujuboside A in Sprague-Dawley rats determined by an efficient HPLC-ESI-MS/MS method[J].J Liq Chromatogr R T,2015,38(2):215-221.
[29]崔瑛,杨晶晶,郭敏娟,等.基于“病证-效应-生物样本分析”方法的酸枣仁“安神”药性物质及归经的研究[J].世界科学技术-中医药现代化,2015,17(3):569-577.
[30]郭敏娟.酸枣仁对阴虚大鼠焦虑行为的影响及指标成分体内分布观察[D].郑州:河南中医学院,2014.
[31]Li H K,Zhou M M,Zhao A H,et al.Traditional Chinese medicine:Balancing the gut ecosystem[J].Phytother Res,2009,23(9):1332-1335.
[32]Ridaura V,Belkaid Y.Gut microbiota:The link to your second brain[J].Cell,2015,161(2):193-194.
[33]Jiang J G,Huang X J,Chen J,et al.Comparison of the sedative and hypnotic effects of flavonoids,saponins,and polysaccharides extracted from Semen Ziziphus Jujube[J].Nat Prod Res,2007,21(4):310-320.
[34]马桂劼,张妍,张明春,等.HPLC-MS/MS法研究大鼠胃内容物对酸枣仁皂苷A的体外代谢作用[J].食品研究与开发,2013,34(19):1-4.
[35]Zhang Y Q,Zhang Y,Zhang K S,et al.Degradation kinetics of jujuboside B by rat intestinal flora in vitro with an RRLC-MS-MS method[J].J Chromatogr Sci,2014,52(7):1-6.
[36]Zhang Y,Xie J B,Zhang Y Q,et al.Degradation kinetics of jujuboside A by rat intestinal flora and identification of the metabolites by HPLC-MS/MS[J].Int J F Prop,2014,17(8):1841-1849.
[37]张群.酸枣仁总皂苷的提取纯化及酸枣仁皂苷A的生物转化研究[D].济南:山东中医药大学,2016.
[38]马桂劼.酸枣仁皂苷A引起的肠道和主要脏腑之间的信息交流[D].天津:天津商业大学,2014.
[39]Zhang T,Xie J B,Zhang Y Q,et al.High performance liquid chromatography coupled with tandem mass spectrometry applied for metabolic study of spinosin by rat intestinal flora[J].J Liq Chromatogr R T,2013,36(10):1391-1400.
[40]Song P P,Zhang Y Q,Qiao L D,et al.A new HPLC-MS/MS method for investigating degradation kinetics of 6'''-feruloylspinosin and identifying its metabolites by rat intestinal bacterial flora in vitro[J].JLiq Chromatogr R T,2016,39(15):724-729.
[41]Jiao L J,Li Y X,Zhang Y Q,et al.Degradation kinetics of 6'''-p-coumaroylspinosin and identification of its metabolites by rat intestinal flora[J].J Agr Food Chem,2017,65(22):1-31.
[42]Vollmer M,Esders S,Farquharson F M,et al.Mutual interaction of phenolic compounds and microbiota:metabolism of complex phenolic apigenin C-and kaempferol O-derivatives by human fecal samples[J].JAgr Food Chem,2018,66(2):1-46.
[43]张巧月.基于液质联用技术的酸枣仁多组分分析与体外代谢研究及连翘心质量标准的建立[D].石家庄:河北医科大学,2016.
[44]Bao K D,Li P,Qi L W,et al.Characterization of flavonoid metabolites in rat plasma,urine,and feces after oral administration of Semen Ziziphi Spinosae extract by HPLC-diode-array detection(DAD)and ion-trap mass spectrometry(MS(n))[J].Chem Pharm Bull,2009,57(2):144-148.
[45]张雷,向诚,王邠,等.酸枣仁总黄酮在大鼠尿液和粪便中的代谢与排泄[J].中国中药杂志,2009,34(3):340-343.
[46]Ren Y,Wang P J,Wu C S,et al.Identification of the metabolites after oral administration of extract of Ziziphi Spinosae Semen to rats or dogs by high-performance liquid chromatography/linear ion trap FTICR hybrid mass spectrometry[J].Biomed Chromatogr,2013,27(1):17-26.
[47]李强,杜晨晖,张敏,等.血清化学与网络药理学关联研究酸枣仁的体内效应成分[J].中草药,2017,48(10):1936-1943.
[48]闫艳,李强,杜晨晖,等.基于体内-体外物质组关联分析酸枣仁潜在效应物质[J].药学学报,2017,52(2):283-290.
[49]王羽凝,穆丽华,许璐,等.基于UPLC-Q-TOF-MSE分析芍枣胶囊在大鼠体内的代谢产物[J].中国实验方剂学杂志,2016,22(20):77-81.
[50]王晶娟,刘洋,赵保胜,等.中药“质效代关联”研究方法与理论的建立[J].中草药,2014,45(11):1507-1510.
[51]刘昌孝,陈士林,肖小河,等.中药质量标志物(Q-Marker):中药产品质量控制的新概念[J].中草药,2016,47(9):1443-1457.
[52]胡明亚.酸枣仁的药理作用及现代临床应用研究[J].中医临床研究,2012,4(19):20.
[53]Zhang J W,Zhou F,Wu X L,et al.Cellular pharmacokinetic mechanisms of adriamycin resistance and its modulation by 20(S)-ginsenoside Rh2 in MCF-7/Adr cells[J].Brit J Pharmacol,2012,165(1):120-134.
[54]乔雪,果德安,叶敏.中药体内代谢研究的思路与方法[J].世界科学技术-中医药现代化,2014,16(3):532-537.
[55]Xing R,Zhou L,Xie L,et al.Development of a systematic approach to rapid classification and identification of notoginsenosides and metabolites in rat feces based on liquid chromatography coupled triple time-of-flight mass spectrometry[J].Anal Chim Acta,2015,867:56-66.
[56]刘洋,潘艳丽,王晶娟,等.多成分药物代谢理论及技术方法分析[J].中草药,2014,45(12):1663-1667.
[57]杨秀伟.基于体内过程的中药有效成分和有效效应物质的发现策略[J].中国中药杂志,2007,32(5):365-370.
[58]Xie T,Liang Y,Hao H P,et al.Rapid identification of ophiopogonins and ophiopogonones in Ophiopogon Japonicus extract with a practical technique of mass defect filtering based on high resolution mass spectrometry[J].J Chromatogr A,2012,1227(5):234-244.
[59]Xue Q,Qi W,Shuang W,et al.Compound to extract to formulation:A knowledge-transmitting approach for metabolites identification of Gegen-Qinlian Decoction,a traditional Chinese medicine formula[J].Sci Rep,2016,6:39534.
[60]Qiao X,Ye M,Xiang C,et al.Analytical strategy to reveal the in vivo process of multi-component herbal medicine:A pharmacokinetic study of licorice using liquid chromatography coupled with triple quadrupole mass spectrometry[J].J Chromatogr A,2012,1258(19):84-93.