王广基中药药代动力学的研究

中药复方药代动力学研究探讨从PK标记物群到临床合理用药设计王广基中国药科大学报告内容中药药代动力学研究意义研究思路关键技术的研究确有疗效中药制剂药代动力学研究体内处置阐明中药在生物体内的物质组处置过程、沟通体内外物质组关系，揭示中药在生物体内的药效物质组，在创新中药、组分中药及现代复方中药研究中具有重要意义药效学药效指标起效植物化学中药效应组分中药复方中药药代动力学一、中药药代动力学研究意义二、研究思路体外物质组体内物质组有效物质组PK/PD标记物多成分整合PK临床PPK/PPD临床合理用药中药药代动力学的纵贯式研究三、关键技术的研究体外物质组体内物质组有效物质组PK/PD标记物多成分整合PK临床PPK/PPD临床合理用药定性定量分析及体内外物质组关联技术PK/PD筛选整体药效评价化学/生物信息多成分整合PK/PD模型系列成分构动关系中西药相互作用2019年获批筹建国家中医药管理局中药复方药代动力学方法学重点研究室，获国家重大专项课题“中药复方药代动力学关键技术”资助。核心分析思想：中药成分通常以类群存在，具有相同母核结构或共有结构单元，形成相同碎片离子，根据共有离子进行成分分类。利用LC-MS/IT-TOF的精确分子量功能，预测成分的化学式，在网络/光盘成分库中进行查寻符合的结构式（几十个-几百个不等）；基于所有碎片离子，应用自编的（基于Matlab平台）的共有离子搜寻软件，根据共有离子信息对化合物进行分类与桥接；确定共有离子化学结构，根据亚结构信息，对数据库中所获得的候选结构进行再筛选，进而根据碎裂规律推测化合物结构。1.中药复杂未知成分快速鉴定技术1.中药复杂未知成分快速鉴定技术人参皂苷五味子木脂素基于部分对照品确定各类成分诊断离子JMassSpectrom,2009,44:230-44AnalChem,2019;80:8187-941.中药复杂未知成分快速鉴定技术脉络宁注射液成分分类OOOHOR2OR1GlcOOR1R264HH87Glc-GlcX5X5=R1R2OR3OHR1R2R31CH2HH2OHH3OOHH28OOHGlcOOHRR69H73FormylR1OR2R1R2Doublebonds49Xyl-GlcHΔ3,450Xyl-GlcH－62Glc-GlcOHΔ3,434O-Glc-AraR1R2R3R4Doublebonds7HHHOH-10OHHHOHΔ2,334HGlcCH3H-R2OR423OHOR1R3OR3R4OR1R1R2R3R4R5R6Doublebonds14HHOHHOHHΔ7,841GlcHHHOHHΔ7,844GlcHHOHHH－47GlcHOHHOHHΔ7,851GlcCH3OHHOHHΔ7,853GlcCH3OHHCH2OHHΔ7,854GlcHOHVinylOHCH3Δ7,858GlcHHOHCH2COOHH－61GlcCH3OHOCH3OHH－71GlcHOH3,4-dihydroxylphenylOHHΔ7,8R5R6OOR278OR2R1R3HOR434R1R2R3R4Doublebonds20HHHCHCOOHΔ3,422OHHHCHCOOHΔ3,431HCOOHEthynylCHCOOHΔ3,457OHCH2OHHO-Glc－OOOR5OR1OR3OHR2OOR4R1R2R3R4R529HHHHH65HHRhaHH68HHRhaCH3H82HCaffeoylRhaHH83HCaffeoylRhaCH3H84HFeruloylRhaCH3H86AraFeruloylRhaHCH3OOHOR3R2OR1OOOHR4R1R2R3R4Doublebonds32HHHHΔ1,233HOHHH－36HOHHOH－39HOHHOCH3－75HOHCaffeoylOH－12R1R2R3R4R5R6R7Doublebonds38OHOHCH3OHVinylHH-48OHCH3CH3HOCH3CH3OCH3-55HHGlcHHHHΔ2,363HHGlcHOHHHΔ2,380HHGlc-RhaHHHHΔ2,381HHGlc-RhaHOHHHΔ2,385HX4HHOHGlcHΔ2,3OOHOR3OOR6R5R1R2R4R723OOOHOHOHOHOX4=OHOHOOOHOHHOOHOHR45RDoublebonds74HΔ4,577OH-脉络宁注射液的制剂成分分析成分类别个数有机酸类30糖苷类17环烯醚萜类10黄酮类10苯乙醇苷类7醌类4生物碱类3甾酮类3Peerreviewers:Theworkisimportant,originalandinteresting.Inmyopiniontheapproachisverycleverandoriginal.DrugWeek以“StudyfromChinaPharmaceuticalUniversityprovidenovelinsightintoliquidchromatography”为题专文评价了该项策略2.中药多成分同步定量分析技术化合物名称方法最低定量限发表论文人参皂苷Rg1、Rh1、PPTLC-MS1.0ng/mlJPharmBiomedAnalRg1,Re,Rd,Rb1,麦冬皂苷DLC-MS6.0ng/mlJChromatogrB丹参酮IIA，IIB,羟基IIA,紫丹参甲素LC-MS/MS1.0ng/mlRapidCommunMassSpectrom隐丹参酮、丹参酮ⅡALC-MS/MS1.0ng/mlJPharmBiomedAnal氧化苦参碱、苦参碱LC-MS2.0ng/mlJChromatogrB人参皂苷Rg3、Rh2、ppdLC-MS10ng/mLJChromatogrB绿原酸，咖啡酸,二咖啡酰奎宁酸（3种异构体）LC-MS50ng/mlBiomedChromatogr0.00.11.010.0100.01000.00.005.0010.0015.0020.0025.00时间(h)浓度(ng/ml)549.1497.1613.1441.1441.1455.1455.1555.1555.1525.2525.2471.1471.1553.1553.1523.1537.1537.1559.1537.1409.10.11.010.0100.01000.00510152025时间(h)浓度(ng/ml)SchisandrinSchisantherinASchisandrinBDeoxyschizandrinγ-SchisandrinAngeloylgomisinHAngeloylgomisinPLC-MS-IT-TOF法同时测定28种木脂素，对其中有标准品的7种成分进行了精确定量分析,另21种没有标准品的成分进行相对定量分析,LLOQ1ng/mL2.中药多成分同步定量分析技术针对标准品不易获得，建立粗提物“稀释比标准曲线法”定量分析方法3.中药成分代谢产物快速分析技术Talanta,2009,80:572-80松果菊苷降解产物降解产物的I/II相代谢产物I/II相代谢产物级联代谢产物(Sequentialmetabolites)分析策略研究药后血浆指纹谱空白血浆指纹谱药源性指纹谱制剂指纹谱原形成分组代谢产物组制剂成分组代谢物归属与确定代谢途径不同时相药效物质组应用自编的化学信息处理软件，包括差示谱分析软件及代谢物与原形成分关联分析软件3.中药成分代谢产物快速分析技术脉络宁注射液体内外物质组关联分析代谢物代谢物化学结构代谢途径M15-Hydroxymethyl-2-furancarboxylicacidY(5-Hydroxymethylfuraldehyde)+OM23-Methyl-1H-pyrrole-2,4-dicarboxylicacidY11_C2H4_CH2M3Oospolide?M42-(1-Hydroxypropan-2-yl)-4-oxocyclopentanecarboxylicacidY7_2HM5Glucuronicacid?M64-HydroxybenzamidoaceticacidY3_O+GlyM72-Hydroxy-3-(4-methoxyphenyl)propanoicacidY4+2H+O+CH2M84-(Methoxycarbonyl)-3-(hydroxymethyl)-1H-pyrrole-2-carboxylicacidY11_C2H4+OM92-(1-Formylethyl)-2-hydroxy-4-oxocyclopentanecarboxylicacidY10_2HM102,4-Bis(hydroxymethyl)-6-methylenecyclohexanecarboxylicacidY13_H2OM1105-O-Glucuronopyranoside-3,4,7-trimethoxy-2-(3,4,5-trimethoxyphenyl)-6-methylchroman-5-olY48+2H+2CH2+GAM1112-(1-Hydroxyethyl)-3-hydroxy-5,7-dimethoxy-1,4-naphthoquinone+2GAY67_-----+2GAM1124'-Methoxy-5-O-acetylscolymosideY81+CH2+O+ACM113Oleanolicacid+2GA???Y(Oleanolicacid)+2GAM114CandidosideY(Oleanolicacid)_O+2H+2Glc+Ara+XylM1153-O-Glucopyranosyl-glucopyranosyl-glucopyranosyl-glucopyranoside-12-oleanene-3,28-diolY(Oleanolicacid)_O+2H+4Glc对其中80%以上的代谢物成功地进行了代谢途径推断及与原形成分的关联分析大鼠血浆中脉络宁注射液代谢网络分析+Rha+GlcOHOHOOHOHOHOOHOHOP6P9P4+O+CH2OHHOOOHOHHOOHHOO-GlcP3P1P29-Glc-H2OOHHOO-Glc-RhaP65HOO-GlcM25HOO-Glc-ApiM60-O-O+ApiOHHOO-GlcM39OHHOO-GlcM41OOHOO-GlcM45O+CH2+CH2OOHHOO-Glc-AraM69+AraOHHOO-GAM33-Glc+GAHOOH+2OO-GAHOM31HO+O+GAOHHOO-GAM28OHGlc-OOOHP28OHHOOP2-O+H2+GAOHGlc-OOHM26OCH3Glc-OOO-GAM77HOHNOHOOM4-O+GlyHOOO-GAM27O-GAHOM24-O+GA-CO2+GAOHOOO-GAM37+CH2+GACaffeoyl-OOHO-CaffeoylHOOHOP75Feruloyl-OOHAC-OOHOM86+2CH2+ACO-GAOHM38OOHOHOM13O+CH2OOOGA-OHOM55O+GAOOOHOHO-RhaOHCaffeoyl-OOHP82M87OOOHOHO-RhaOHCoumaroyl-OO-Feruloyl-2OOHOOSuc-OHOM76OO-GAOHM48OGA-OO-ACOOGA-OOHOM58M47OH+H2O+Suc+GA+AC+H2+GAOGA-OOHHOM43OGA-OOHM36+H2+GA+H2+GA+O+CH2M5OHOOOHOOHOHHOOOHOO-GlcHOOOHOO-GlcOOHOOHOO-GlcOOHO-GlcHOOOHOOOOOOO-GlcOOOHM84P44P41P14M78OO-GlcOOHOOOHM80OO-GlcOOHOOOM83OO-GlcOOHOOOH+CH2OM85OO-GlcOOOOOHO+CH2O+CH2P61P58OOHO-GlcHOOOM71HO+OOOHOO-GlcHOOM70H