首页 期刊 论文 学科刊群 资讯 加盟 关于
EN
image
Article(id=1218551231321129852, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1218551229794403031, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2018-0343, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1526140800000, receivedDateStr=2018-05-13, revisedDate=1531756800000, revisedDateStr=2018-07-17, acceptedDate=null, acceptedDateStr=null, onlineDate=1768454853134, onlineDateStr=2026-01-15, pubDate=1536681600000, pubDateStr=2018-09-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1768454853134, onlineIssueDateStr=2026-01-15, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1768454853134, creator=13701087609, updateTime=1768454853134, updator=13701087609, issue=Issue{id=1218551229794403031, tenantId=1146029695717560320, journalId=1189982191388893191, year='2018', volume='53', issue='9', pageStart='1387', pageEnd='1582', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1768454852770, creator=13701087609, updateTime=1768457118357, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1218560732426322043, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1218551229794403031, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1218560732426322044, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1218551229794403031, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1536, endPage=1544, ext={EN=ArticleExt(id=1218551231820252077, articleId=1218551231321129852, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Identification of major bioactive components and their metabolites in rat plasma after oral administration of Zhikebao tablet by UHPLC-QTOF-MS, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=ORIGINAL ARTICLES, runingTitle=null, highlight=null, articleAbstract=

An ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) method was established to identify the metabolites in rat plasma after oral administration of Zhikebao tablets. The high-resolution mass spectrometer was operated in positive and negative ion mode, respectively. First, full-scan was applied, which was dependent on a multiple mass defect filter (MMDF) combined with dynamic background subtraction (DBS). These were utilized to trigger the information dependent acquisition (IDA) function in the experiment. For the IDA criteria, the eight most intense candidate ions of per cycle were selected to do a product ion scan. Then Metabolite Pilot 2.0 software was utilized to load data to seek possible metabolites. The analytical models employed by Metabolite pilot 2.0 were established for representative compounds of the Papaveris Pericarpium and licorice in Zhikebao tablet. Finally, metabolites were identified according to accurate mass measurement and retention time. 38 components from the rat plasma after oral administration of the drug have been found, including 5 prototype opium alkaloids, liquiritin, glycyrrhizic acid and 31 relative metabolites. The metabolic transformation of Zhikebao tablet in rats was mainly induced by glucuronidation, sulfation, methylation, amine to carboxylic acid, hydrolysis and so on. In this paper, the metabolites of the main active components of Zhikebao tablet were tentatively identified, and the metabolic pathway was compared with that of single chemical drugs. Moreover, it laid the fundamental elucidation of further metabolism study of Zhikebao tablet or other compound traditional Chinese medicine preparations which containing Papaveris Pericarpium or licorice.

, correspAuthors=Qing-yan LI, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2018 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Shi QIAO, Hai-shan XU, Xiao-wei SHI, Wei WANG, Qing-yan LI), CN=ArticleExt(id=1218551233602830427, articleId=1218551231321129852, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=UHPLC-QTOF-MS法分析鉴定止咳宝片在大鼠血浆中的代谢产物, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

采用UHPLC-QTOF-MS技术分析大鼠灌胃给予止咳宝片后的血浆生物样本。首先，在正、负离子模式下分别全扫描，通过信息依赖采集触发子离子的采集，每一循环采集8个最强峰的二级质谱图。采集时进行，实时多重质量亏损和动态背景扣除。其次，应用Metabolite Pilot 2.0软件对止咳宝片君药罂粟壳，配伍药物甘草中主要化学成分为目标建立分析模型，分析各成分的保留时间、精确分子质量、二级质谱信息，对代谢产物进行解析。鉴定5个阿片类生物碱、甘草苷和甘草酸，及其相关代谢产物31个。5种阿片类生物碱、甘草苷和甘草酸在大鼠体内的代谢途径包括葡萄糖醛酸化、硫酸化、脱甲基化、脱氨基甲基后羧基化、水解等。本文从定性角度对复方中药制剂中主要活性成分的体内代谢开展研究，并与已有单一化学药物代谢途径比较，为进一步阐明止咳宝片或含罂粟壳、甘草类复方中药制剂体内代谢过程提供基础。

, correspAuthors=李清艳, authorNote=null, correspAuthorsNote=
* 李清艳, Tel:86-10-85762630, E-mail:
, copyrightStatement=版权所有©《药学学报》编辑部2018, copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=iDSIi89vVAFFddA5aEYYXQ==, magXml=e+sp2HD0igBAteyZ9JJeog==, pdfUrl=null, pdf=vqxGyV+UNCXa3i+XL606VA==, pdfFileSize=485854, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=k5DjUiPGIaNQmQ+IPYAm5Q==, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=OK2jgQiREoibOIZuK92vnw==, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=乔湜, 许海山, 石晓伟, 王伟, 李清艳)}, authors=[Author(id=1218970832827761514, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, orderNo=0, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1218970832991339386, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, authorId=1218970832827761514, language=EN, stringName=Shi QIAO, firstName=Shi, middleName=null, lastName=QIAO, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=1, address=1. Civil Aviation Medical Center, Civil Aviation Administration of China(Civil Aviation General Hospital), Beijing 100123, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1218970833146528645, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, authorId=1218970832827761514, language=CN, stringName=乔湜, firstName=湜, middleName=null, lastName=乔, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=1, address=1.中国民用航空局民用航空医学中心 (民航总医院), 北京 100123, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1218970832534160198, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, xref=null, ext=[AuthorCompanyExt(id=1218970832550937416, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, companyId=1218970832534160198, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1. Civil Aviation Medical Center, Civil Aviation Administration of China(Civil Aviation General Hospital), Beijing 100123, China), AuthorCompanyExt(id=1218970832576103245, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, companyId=1218970832534160198, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1.中国民用航空局民用航空医学中心 (民航总医院), 北京 100123)])]), Author(id=1218970833268163477, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, orderNo=1, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1218970833427547043, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, authorId=1218970833268163477, language=EN, stringName=Hai-shan XU, firstName=Hai-shan, middleName=null, lastName=XU, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=1, address=1. Civil Aviation Medical Center, Civil Aviation Administration of China(Civil Aviation General Hospital), Beijing 100123, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1218970833515627435, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, authorId=1218970833268163477, language=CN, stringName=许海山, firstName=海山, middleName=null, lastName=许, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=1, address=1.中国民用航空局民用航空医学中心 (民航总医院), 北京 100123, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1218970832534160198, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, xref=null, ext=[AuthorCompanyExt(id=1218970832550937416, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, companyId=1218970832534160198, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1. Civil Aviation Medical Center, Civil Aviation Administration of China(Civil Aviation General Hospital), Beijing 100123, China), AuthorCompanyExt(id=1218970832576103245, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, companyId=1218970832534160198, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1.中国民用航空局民用航空医学中心 (民航总医院), 北京 100123)])]), Author(id=1218970833658233784, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, orderNo=2, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1218970833830200266, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, authorId=1218970833658233784, language=EN, stringName=Xiao-wei SHI, firstName=Xiao-wei, middleName=null, lastName=SHI, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=2, address=2. School of Pharmacy, Hebei Medical University, Shijiazhuang 050017, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1218970833997972441, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, authorId=1218970833658233784, language=CN, stringName=石晓伟, firstName=晓伟, middleName=null, lastName=石, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=2, address=2.河北医科大学药学院, 河北 石家庄 050017, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1218970832689349466, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, xref=null, ext=[AuthorCompanyExt(id=1218970832706126684, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, companyId=1218970832689349466, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2. School of Pharmacy, Hebei Medical University, Shijiazhuang 050017, China), AuthorCompanyExt(id=1218970832714515294, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, companyId=1218970832689349466, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.河北医科大学药学院, 河北 石家庄 050017)])]), Author(id=1218970834148967402, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, orderNo=3, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1218970835067519994, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, authorId=1218970834148967402, language=EN, stringName=Wei WANG, firstName=Wei, middleName=null, lastName=WANG, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=1, address=1. Civil Aviation Medical Center, Civil Aviation Administration of China(Civil Aviation General Hospital), Beijing 100123, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1218970835218513925, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, authorId=1218970834148967402, language=CN, stringName=王伟, firstName=伟, middleName=null, lastName=王, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=1, address=1.中国民用航空局民用航空医学中心 (民航总医院), 北京 100123, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1218970832534160198, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, xref=null, ext=[AuthorCompanyExt(id=1218970832550937416, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, companyId=1218970832534160198, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1. Civil Aviation Medical Center, Civil Aviation Administration of China(Civil Aviation General Hospital), Beijing 100123, China), AuthorCompanyExt(id=1218970832576103245, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, companyId=1218970832534160198, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1.中国民用航空局民用航空医学中心 (民航总医院), 北京 100123)])]), Author(id=1218970835335954451, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, orderNo=4, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=liqingyan@camc-caac.com, emailSecond=null, emailThird=null, correspondingAuthor=1, authorType=1, ext={EN=AuthorExt(id=1218970835474366494, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, authorId=1218970835335954451, language=EN, stringName=Qing-yan LI, firstName=Qing-yan, middleName=null, lastName=LI, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=1, *, address=1. Civil Aviation Medical Center, Civil Aviation Administration of China(Civil Aviation General Hospital), Beijing 100123, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1218970835604389935, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, authorId=1218970835335954451, language=CN, stringName=李清艳, firstName=清艳, middleName=null, lastName=李, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=1, *, address=1.中国民用航空局民用航空医学中心 (民航总医院), 北京 100123, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1218970832534160198, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, xref=null, ext=[AuthorCompanyExt(id=1218970832550937416, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, companyId=1218970832534160198, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1. Civil Aviation Medical Center, Civil Aviation Administration of China(Civil Aviation General Hospital), Beijing 100123, China), AuthorCompanyExt(id=1218970832576103245, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, companyId=1218970832534160198, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1.中国民用航空局民用航空医学中心 (民航总医院), 北京 100123)])])], keywords=[Keyword(id=1218970835847659590, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, language=EN, orderNo=1, keyword=Zhikebao tablet), Keyword(id=1218970835981877334, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, language=EN, orderNo=2, keyword=Papaveris Pericarpium), Keyword(id=1218970836099317859, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, language=EN, orderNo=3, keyword=UHPLC-QTOF-MS), Keyword(id=1218970836191592556, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, language=EN, orderNo=4, keyword=metabolites), Keyword(id=1218970836279672953, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, language=EN, orderNo=5, keyword=opium alkaloids), Keyword(id=1218970836409696392, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, language=EN, orderNo=6, keyword=licorice), Keyword(id=1218970836518748305, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, language=CN, orderNo=1, keyword=止咳宝片), Keyword(id=1218970836594245790, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, language=CN, orderNo=2, keyword=罂粟壳), Keyword(id=1218970836703297704, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, language=CN, orderNo=3, keyword=UHPLC-QTOF-MS), Keyword(id=1218970836795572406, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, language=CN, orderNo=4, keyword=代谢产物), Keyword(id=1218970836984316104, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, language=CN, orderNo=5, keyword=阿片类生物碱), Keyword(id=1218970837076590802, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, language=CN, orderNo=6, keyword=甘草)], refs=[Reference(id=1218970839387652500, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[1], rfOrder=0, authorNames=null, journalName=null, refType=null, unstructuredReference=Chinese Pharmacopoeia Commission. Pharmacopoeia of the People's Republic of China (中华人民共和国药典)[S]. Vol 1. 2015 ed. Beijing: China Medical Science Press, 2015: 624., articleTitle=null, refAbstract=null), Reference(id=1218970839471538584, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[2], rfOrder=1, authorNames=null, journalName=null, refType=null, unstructuredReference=Chen M. Clinical application and management of Papaver somniferum[J]. China Pharm (中国药房), 2016, 27: 3461-3463., articleTitle=null, refAbstract=null), Reference(id=1218970839588979099, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[3], rfOrder=2, authorNames=null, journalName=null, refType=null, unstructuredReference=Liu GR, Qiao S, Liu TB, et al. Simultaneous determination of 18 chemical constituents in traditional Chinese medicine of antitussive by UPLC-MS-MS[J]. J Chromatogr Sci, 2016, 54: bmw099., articleTitle=null, refAbstract=null), Reference(id=1218970839702225315, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[4], rfOrder=3, authorNames=null, journalName=null, refType=null, unstructuredReference=Geng JL, Dai Y, Yao ZH, et al. Metabolites profile of Xian-Ling-Gu-Bao capsule, a traditional Chinese medicine prescription, in rats by ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry analysis[J]. J Pharm Biomed Anal, 2014, 96: 90-103., articleTitle=null, refAbstract=null), Reference(id=1218970839865803178, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[5], rfOrder=4, authorNames=null, journalName=null, refType=null, unstructuredReference=Zheng C, Hao H, Wang X, et al. Diagnostic fragmention-based extension strategy for rapid screening and identification of serial components of homologous families contained in traditional Chinese medicine prescription using high-resolution LC-ESI-IT-TOF/MS: Shengmai injection as an example[J]. J Mass Spectrom, 2009, 44: 230-244., articleTitle=null, refAbstract=null), Reference(id=1218970839970660786, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[6], rfOrder=5, authorNames=null, journalName=null, refType=null, unstructuredReference=Bosch ME, Sánchez AR, Rojas FS, et al. Morphine and its metabolites: analytical methodologies for its determination[J]. J Pharm Biomed Anal, 2007, 43: 799-815., articleTitle=null, refAbstract=null), Reference(id=1218970840088101305, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[7], rfOrder=6, authorNames=null, journalName=null, refType=null, unstructuredReference=Liu YZ. Metabolism of morphine in vivo[J]. Heilongjiang Med J (黑龙江医药), 2010, 23: 252-253., articleTitle=null, refAbstract=null), Reference(id=1218970840176181694, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[8], rfOrder=7, authorNames=null, journalName=null, refType=null, unstructuredReference=Li L, Chen XY, Zhong DF. Applications of liquid chromatography-mass spectrometry in drug metabolite identification[J]. J Chin Mass Spectrom Soc (质谱学报), 2017, 38: 375-387., articleTitle=null, refAbstract=null), Reference(id=1218970840276844996, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[9], rfOrder=8, authorNames=null, journalName=null, refType=null, unstructuredReference=Wang YX, Hao HP, Wang GJ. Application of Q-TOF and IT-TOF mass spectrometry technology in identifying the natural products and the biological metabolites[J]. Chin J Nat Med, 2009, 7: 394-400., articleTitle=null, refAbstract=null), Reference(id=1218970840364925386, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[10], rfOrder=9, authorNames=null, journalName=null, refType=null, unstructuredReference=Wang N, Hassan H, Jia YM, et al. Identification of polygala oligosaccharide esters and their metabolites in rat plasma after oral administration of ethanol extract of Kai Xin San by UHPLC-MS[J]. Acta Pharm Sin (药学学报), 2017, 52: 1592-1598., articleTitle=null, refAbstract=null), Reference(id=1218970840469782992, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[11], rfOrder=10, authorNames=null, journalName=null, refType=null, unstructuredReference=Cheng YX, Chen LJ, Wang ZM, et al. Analysis of major bioactive components and their metabolites in rats' plasma, urine and feces after oral administration of the aqueous extract of Euodiae Fructus by UHPLC-QTOF-MS[J]. Acta Pharm Sin (药学学报), 2017, 52: 1157-1164., articleTitle=null, refAbstract=null), Reference(id=1218970840562057686, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[12], rfOrder=11, authorNames=null, journalName=null, refType=null, unstructuredReference=Su LL, Cheng X, Ji D, et al. Analysis of lignans and their metabolites derived from Schisandra chinensis and vinegar Schisandra chinensis in rats' plasma, bile, urine and faeces based on UHPLC-QTOF/MS[J]. Acta Pharm Sin (药学学报), 2016, 51: 1600-1608., articleTitle=null, refAbstract=null), Reference(id=1218970840662720987, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[13], rfOrder=12, authorNames=null, journalName=null, refType=null, unstructuredReference=Li J, Hua ZD, Wang YM. Analysis of metabolites and metabolic pathway of 5F-AMB in vitro using UPLC-HR-MS[J]. Acta Pharm Sin (药学学报), 2017, 52: 1743-1747., articleTitle=null, refAbstract=null), Reference(id=1218970840750801376, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[14], rfOrder=13, authorNames=null, journalName=null, refType=null, unstructuredReference=Zhang Z, Yan B, Liu K, et al. Fragmentation pathways of heroin-related alkaloids revealed by ion trap and quadrupole time-of-flight tandem mass spectrometry [J]. Rapid Commun Mass Spectrom, 2008, 22: 2851-2862., articleTitle=null, refAbstract=null), Reference(id=1218970840872436200, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[15], rfOrder=14, authorNames=null, journalName=null, refType=null, unstructuredReference=Xiang C, Qiao X, Wang Q, et al. From single compounds to herbal extract: a strategy to systematically characterize the metabolites of licorice in rats [J]. Drug Metab Dispos, 2011, 39: 1597-1608., articleTitle=null, refAbstract=null), Reference(id=1218970840968905197, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[16], rfOrder=15, authorNames=null, journalName=null, refType=null, unstructuredReference=Xie PS, Leung AY. Understanding the traditional aspect of Chinese medicine in order to achieve meaningful quality control of Chinese materia medica[J]. J Chromatogr A, 2009, 1216: 1933-1940., articleTitle=null, refAbstract=null)], funds=[Fund(id=1218970839173742979, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, awardId=DFS20160604, language=CN, fundingSource=民航安全能力建设基金资助项目(DFS20160604), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1218970832534160198, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, xref=null, ext=[AuthorCompanyExt(id=1218970832550937416, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, companyId=1218970832534160198, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1. Civil Aviation Medical Center, Civil Aviation Administration of China(Civil Aviation General Hospital), Beijing 100123, China), AuthorCompanyExt(id=1218970832576103245, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, companyId=1218970832534160198, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1.中国民用航空局民用航空医学中心 (民航总医院), 北京 100123)]), AuthorCompany(id=1218970832689349466, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, xref=null, ext=[AuthorCompanyExt(id=1218970832706126684, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, companyId=1218970832689349466, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2. School of Pharmacy, Hebei Medical University, Shijiazhuang 050017, China), AuthorCompanyExt(id=1218970832714515294, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, companyId=1218970832689349466, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.河北医科大学药学院, 河北 石家庄 050017)])], figs=[ArticleFig(id=1218970837328249067, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, language=EN, label=null, caption=null, figureFileSmall=ZYF1d4hmTiccQWYXdCWZwQ==, figureFileBig=u/+m0lwSfPtSU3T++/rbyw==, tableContent=null), ArticleFig(id=1218970837428912369, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, language=CN, label=Figure 1, caption=

Total ion chromatogram (TIC) of Zhikebao Tablet in positive mode. (A) TIC of morphine-related metabolites; (B) TIC of codeine-related metabolites; (C) The possible metabolic pathways of morphine and codeine. The peak numbers were in accordance with Table 1

, figureFileSmall=ZYF1d4hmTiccQWYXdCWZwQ==, figureFileBig=u/+m0lwSfPtSU3T++/rbyw==, tableContent=null), ArticleFig(id=1218970837563130116, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, language=EN, label=null, caption=null, figureFileSmall=rTdc8Bstpp8Lnf40Al/Dhw==, figureFileBig=wFXI9jLv2V5Qr6rK0dHfxw==, tableContent=null), ArticleFig(id=1218970837709930767, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, language=CN, label=Figure 2, caption=

TIC of Zhikebao Tablet in positive mode. (A) TIC of thebaine-related metabolites; (B) The possible metabolic pathways of thebaine. The peak numbers were in accordance with Table 1

, figureFileSmall=rTdc8Bstpp8Lnf40Al/Dhw==, figureFileBig=wFXI9jLv2V5Qr6rK0dHfxw==, tableContent=null), ArticleFig(id=1218970837806399768, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, language=EN, label=null, caption=null, figureFileSmall=SaZUZ7b85UgfWsVC0zRtJQ==, figureFileBig=Rptyfll0PCrhI9igKaHNZg==, tableContent=null), ArticleFig(id=1218970837911257374, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, language=CN, label=Figure 3, caption=

TIC of Zhikebao Tablet in positive mode. (A) TIC of papaverine-related metabolites; (B) The possible metabolic pathways of papaverine. The peak numbers were in accordance with Table 1

, figureFileSmall=SaZUZ7b85UgfWsVC0zRtJQ==, figureFileBig=Rptyfll0PCrhI9igKaHNZg==, tableContent=null), ArticleFig(id=1218970838020309288, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, language=EN, label=null, caption=null, figureFileSmall=b0VNSO/S2uvILdToE/bkMw==, figureFileBig=/I4iQfMx5MDVJ2IHcFj3xA==, tableContent=null), ArticleFig(id=1218970838175498550, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, language=CN, label=Figure 4, caption=

TIC of Zhikebao Tablet in positive mode. (A) TIC of nascapine-related metabolites; (B) The possible metabolic pathways of nascapine. The peak numbers were in accordance with Table 1

, figureFileSmall=b0VNSO/S2uvILdToE/bkMw==, figureFileBig=/I4iQfMx5MDVJ2IHcFj3xA==, tableContent=null), ArticleFig(id=1218970838313910592, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, language=EN, label=null, caption=null, figureFileSmall=Shg5a+JAdYqj35zyBtNyrw==, figureFileBig=nXCIfdtg+kMk/ONS0Ofn/w==, tableContent=null), ArticleFig(id=1218970838431351114, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, language=CN, label=Figure 5, caption=

TIC of Zhikebao Tablet in negative mode. (A) TIC of liquiritin-related metabolites; (B) The possible metabolic pathways of liquiritin. The peak numbers were in accordance with Table 1

, figureFileSmall=Shg5a+JAdYqj35zyBtNyrw==, figureFileBig=nXCIfdtg+kMk/ONS0Ofn/w==, tableContent=null), ArticleFig(id=1218970838573957463, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, language=EN, label=null, caption=null, figureFileSmall=oI9rOY6y2NES0O3mHJXEoA==, figureFileBig=iJf5D2mbyvHFD1HJcFPuCQ==, tableContent=null), ArticleFig(id=1218970838687203678, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, language=CN, label=Figure 6, caption=

TIC of Zhikebao Tablet in negative mode. (A) TIC of glycyrrhizic acid-related metabolites; (B) The possible metabolic pathways of glycyrrhizic acid. The peak numbers were in accordance with Table 1

, figureFileSmall=oI9rOY6y2NES0O3mHJXEoA==, figureFileBig=iJf5D2mbyvHFD1HJcFPuCQ==, tableContent=null), ArticleFig(id=1218970838821421415, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Peak ID Tentative identification Formula m/z ppm tR /min Fragment ion (m/z)
M1 Morphine C17H19NO3 286.145 1 4.6 4.32 229 (C14H13O3), 211 (C14H11O2), 201 (C13H13O2), 185 (C12H9O2), 165 (C13H9)
M1-1 3-Glucuronide conjugation C23H27NO9 462.175 7 -0.2 2.25 286 (C17H20NO3), 268 (C17H18NO2), 229 (C14H13O3), 211 (C14H11O2)
M1-2 6-Glucuronide conjugation C23H27NO9 462.176 9 2.3 3.11 286 (C17H20NO3), 268 (C17H18NO2), 229 (C14H13O3), 211 (C14H11O2)
M1-3 Loss of CH2 + demethylation C15H17NO3 258.111 5 -4.6 7.57 240 (C15H13NO2), 184 (C12H10NO2),
M1-4 phosphorylation C17H20NO6P 366.109 8 -0.9 8.19 321 (C15H14O6P), 281 (C17H15NO3), 113 (CH6O4P)
M1-5 N-Acetylation C19H21NO4 328.156 0 5.0 9.51 297 (C17H15O4), 237 (C16H13O2), 165 (C13H9)
M1-6 Loss of O + glucuronide conjugation C23H27NO8 446.182 4 3.3 15.47 428 (C23H26NO7), 365 (C18H21O8), 355 (C20H19O6), 352 (C20H16O6), 233 (C17H15N)
M1-7 Loss of O and amine to carboxylic acid C18H18O4 299.126 4 -3.4 21.91 281 (C18H16O3), 151 (C9H11O2), 93 (C7H9)
M1-8 Amine to carboxylic acid C18H18O5 315.122 4 -0.8 23.35 279 (C18H15O3), 123 (C7H7O2), 107 (C7H7O)
M1-9 Loss of O and O and amine to carboxylic acid C18H18O3 283.132 0 -2.9 24.95 223 (C17H19)
M1-10 Loss of O and amine to carboxylic acid C18H18O4 299.126 4 -4.7 27.92 281 (C18H16O3), 151 (C9H11O2), 93 (C7H9)
M2 Codeine C18H21NO3 300.160 1 2.4 7.23 282 (C18H20NO2), 243 (C15H17NO2), 225 (C15H13O2), 215 (C14H15O2), 199 (C13H11O2), 165 (C13H9)
M2-1 Oxidative Deamination to Alcohol C18H20O4 301.142 6 -2.8 34.62 199 (C11H19O3)
M3 Thebaine C19H21NO3 312.158 9 -1.7 12.89 281 (C18H17O3), 266 (C16H21NO3), 58 (C3H8N)
M3-1 Loss of CH2 + glucuronide conjugation C24H27NO9 474.177 0 2.4 5.37 284 (C17H18NO3), 259 (C16H19O3), 249 (C16H11NO2)
M3-2 Loss of CH2 + glucuronide conjugation C24H27NO9 474.175 6 -0.6 6.32 284 (C17H18NO3), 259 (C16H19O3), 249 (C16H11NO2)
M3-3 Loss of 2CH2 and amine to carboxylic acid C18H16O4 297.113 6 4.9 9.49 237 (C16H13O2), 222 (C15H10O2), 205 (C15H9O), 189 (C11H9O3)
M3-4 Sulfate conjugation C19H21NO6S 392.115 2 -2.7 31.39 332 (C17H18NO4S), 330 (C17H16NO4S), 274 (C11H16NO5S), 246 (C17H12NO)
M3-5 Loss of CH2 and amine to carboxylic acid C19H18O5 327.124 0 4.0 36.19 227 (C14H11O3), 121 (C7H5O2)
M4 Papaverine C20H21NO4 340.153 0 -1.8 15.04 324 (C20H21NO3), 202 (C12H12NO2), 187 (C12H13NO), 171 (C11H9NO), 156 (C10H6NO)
M4-1 Loss of 2CH2O + loss of 2H C18H15NO2 278.116 3 -4.3 3.11 215 (C16H9N), 144 (C10H10N), 142 (C10H8N), 130 (C9H8N)
M4-2 Loss of 2CH2 and glucose conjugation C24H27NO9 474.175 6 -0.6 6.32 327 (C19H21NO4), 284 (C17H18NO3), 249 (C16H11NO2)
M4-3 Loss of CH2O + inernal hydrolysis C19H21NO4 328.1560 5.0 9.51 297 (C17H15NO4), 282 (C16H12NO4), 265 (C16H11NO3)
M5 Nascapinet C22H23NO7 414.155 7 2.3 15.20 353 (C20H19NO5), 220 (C12H14NO3), 205 (C11H11NO3), 175 (C11H13NO)
M5-1 Loss of 2CH2O and amine to carboxylic acid C21H18O7 382.114 2 4.5 14.62 308 (C19H16O4), 201 (C12H19O3), 188 (C11H8O3)
M5-2 Loss of 2CH2O and amine to carboxylic acid C21H18O7 382.114 3 4.7 14.84 308 (C19H16O4), 201 (C12H19O3), 188 (C11H8O3)
M5-3 Amine to carboxylic acid C23H22O9 442.131 6 -4.6 16.95 267 (C13H15O6), 199 (C12H7O)
M6 Liquiritin C21H22O9 417.117 1 -4.8 14.81 255 (C15H11O4), 241 (C15H13O3), 135 (C8H7O2), 121 (C7H5O2)
M6-1 Sulfate conjugation C21H22O12S 497.074 0 -3.9 12.03 417 (C21H21O9), 321 (C15H13O6S), 241 (C15H13O3), 175 (C6H7O6)
M6-2 Hydrogenation C21H24O9 419.132 9 -4.3 16.92 243 (C15H15O3), 175 (C6H7O6), 117 (C4H5O4)
M6-3 Loss of C6H10O5 C15H12O4 255.065 8 -1.8 17.95 135 (C8H7O2), 119 (C8H7O)
M6-4 Internal hydrolysis and di-oxidation C21H24O12 467.117 2 -5 19.35 421 (C20H21O10), 399 (C18H23O10), 256 (C15H12O4)
M6-5 Loss of 2O C21H22O7 385.128 5 -2 22.85 249 (C17H13O2), 119 (C8H7O)
M6-6 Loss of C6H10O5 C15H12O4 255.065 2 -4.2 23.33 135 (C8H7O2), 119 (C8H7O)
M6-7 Loss of O and O and methylation C22H24O7 399.145 3 0.9 25.10 217 (C16H9O), 163 (C6H11O5)
M7 Glycyrrhizic acid C42H61O16 821.393 7 -3.4 24.48 645 (C36H53O10), 351 (C12H15O12), 289 (C11H13O9), 193 (C6H9O7)
M7-1 Loss of C12H16O13 C30H46O3 453.336 5 -2.1 23.65 407 (C27H35O3), 405 (C28H37O2), 389 (C28H37O), 371 (C24H35O3)
M7-2 Loss of C12H16O12 and oxidation C30H46O5 485.326 1 -2.4 26.93 467 (C29H39O5), 371 (C25H39O2), 291 (C17H23O4), 213 (C12H21O3)
), ArticleFig(id=1218970838976610673, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551231321129852, language=CN, label=Table 1, caption=

Identification of metabolites in rat plasma after a single oral administration of Zhikebao Tablet using UHPLC-Q-TOF/MS

, figureFileSmall=null, figureFileBig=null, tableContent=
Peak ID Tentative identification Formula m/z ppm tR /min Fragment ion (m/z)
M1 Morphine C17H19NO3 286.145 1 4.6 4.32 229 (C14H13O3), 211 (C14H11O2), 201 (C13H13O2), 185 (C12H9O2), 165 (C13H9)
M1-1 3-Glucuronide conjugation C23H27NO9 462.175 7 -0.2 2.25 286 (C17H20NO3), 268 (C17H18NO2), 229 (C14H13O3), 211 (C14H11O2)
M1-2 6-Glucuronide conjugation C23H27NO9 462.176 9 2.3 3.11 286 (C17H20NO3), 268 (C17H18NO2), 229 (C14H13O3), 211 (C14H11O2)
M1-3 Loss of CH2 + demethylation C15H17NO3 258.111 5 -4.6 7.57 240 (C15H13NO2), 184 (C12H10NO2),
M1-4 phosphorylation C17H20NO6P 366.109 8 -0.9 8.19 321 (C15H14O6P), 281 (C17H15NO3), 113 (CH6O4P)
M1-5 N-Acetylation C19H21NO4 328.156 0 5.0 9.51 297 (C17H15O4), 237 (C16H13O2), 165 (C13H9)
M1-6 Loss of O + glucuronide conjugation C23H27NO8 446.182 4 3.3 15.47 428 (C23H26NO7), 365 (C18H21O8), 355 (C20H19O6), 352 (C20H16O6), 233 (C17H15N)
M1-7 Loss of O and amine to carboxylic acid C18H18O4 299.126 4 -3.4 21.91 281 (C18H16O3), 151 (C9H11O2), 93 (C7H9)
M1-8 Amine to carboxylic acid C18H18O5 315.122 4 -0.8 23.35 279 (C18H15O3), 123 (C7H7O2), 107 (C7H7O)
M1-9 Loss of O and O and amine to carboxylic acid C18H18O3 283.132 0 -2.9 24.95 223 (C17H19)
M1-10 Loss of O and amine to carboxylic acid C18H18O4 299.126 4 -4.7 27.92 281 (C18H16O3), 151 (C9H11O2), 93 (C7H9)
M2 Codeine C18H21NO3 300.160 1 2.4 7.23 282 (C18H20NO2), 243 (C15H17NO2), 225 (C15H13O2), 215 (C14H15O2), 199 (C13H11O2), 165 (C13H9)
M2-1 Oxidative Deamination to Alcohol C18H20O4 301.142 6 -2.8 34.62 199 (C11H19O3)
M3 Thebaine C19H21NO3 312.158 9 -1.7 12.89 281 (C18H17O3), 266 (C16H21NO3), 58 (C3H8N)
M3-1 Loss of CH2 + glucuronide conjugation C24H27NO9 474.177 0 2.4 5.37 284 (C17H18NO3), 259 (C16H19O3), 249 (C16H11NO2)
M3-2 Loss of CH2 + glucuronide conjugation C24H27NO9 474.175 6 -0.6 6.32 284 (C17H18NO3), 259 (C16H19O3), 249 (C16H11NO2)
M3-3 Loss of 2CH2 and amine to carboxylic acid C18H16O4 297.113 6 4.9 9.49 237 (C16H13O2), 222 (C15H10O2), 205 (C15H9O), 189 (C11H9O3)
M3-4 Sulfate conjugation C19H21NO6S 392.115 2 -2.7 31.39 332 (C17H18NO4S), 330 (C17H16NO4S), 274 (C11H16NO5S), 246 (C17H12NO)
M3-5 Loss of CH2 and amine to carboxylic acid C19H18O5 327.124 0 4.0 36.19 227 (C14H11O3), 121 (C7H5O2)
M4 Papaverine C20H21NO4 340.153 0 -1.8 15.04 324 (C20H21NO3), 202 (C12H12NO2), 187 (C12H13NO), 171 (C11H9NO), 156 (C10H6NO)
M4-1 Loss of 2CH2O + loss of 2H C18H15NO2 278.116 3 -4.3 3.11 215 (C16H9N), 144 (C10H10N), 142 (C10H8N), 130 (C9H8N)
M4-2 Loss of 2CH2 and glucose conjugation C24H27NO9 474.175 6 -0.6 6.32 327 (C19H21NO4), 284 (C17H18NO3), 249 (C16H11NO2)
M4-3 Loss of CH2O + inernal hydrolysis C19H21NO4 328.1560 5.0 9.51 297 (C17H15NO4), 282 (C16H12NO4), 265 (C16H11NO3)
M5 Nascapinet C22H23NO7 414.155 7 2.3 15.20 353 (C20H19NO5), 220 (C12H14NO3), 205 (C11H11NO3), 175 (C11H13NO)
M5-1 Loss of 2CH2O and amine to carboxylic acid C21H18O7 382.114 2 4.5 14.62 308 (C19H16O4), 201 (C12H19O3), 188 (C11H8O3)
M5-2 Loss of 2CH2O and amine to carboxylic acid C21H18O7 382.114 3 4.7 14.84 308 (C19H16O4), 201 (C12H19O3), 188 (C11H8O3)
M5-3 Amine to carboxylic acid C23H22O9 442.131 6 -4.6 16.95 267 (C13H15O6), 199 (C12H7O)
M6 Liquiritin C21H22O9 417.117 1 -4.8 14.81 255 (C15H11O4), 241 (C15H13O3), 135 (C8H7O2), 121 (C7H5O2)
M6-1 Sulfate conjugation C21H22O12S 497.074 0 -3.9 12.03 417 (C21H21O9), 321 (C15H13O6S), 241 (C15H13O3), 175 (C6H7O6)
M6-2 Hydrogenation C21H24O9 419.132 9 -4.3 16.92 243 (C15H15O3), 175 (C6H7O6), 117 (C4H5O4)
M6-3 Loss of C6H10O5 C15H12O4 255.065 8 -1.8 17.95 135 (C8H7O2), 119 (C8H7O)
M6-4 Internal hydrolysis and di-oxidation C21H24O12 467.117 2 -5 19.35 421 (C20H21O10), 399 (C18H23O10), 256 (C15H12O4)
M6-5 Loss of 2O C21H22O7 385.128 5 -2 22.85 249 (C17H13O2), 119 (C8H7O)
M6-6 Loss of C6H10O5 C15H12O4 255.065 2 -4.2 23.33 135 (C8H7O2), 119 (C8H7O)
M6-7 Loss of O and O and methylation C22H24O7 399.145 3 0.9 25.10 217 (C16H9O), 163 (C6H11O5)
M7 Glycyrrhizic acid C42H61O16 821.393 7 -3.4 24.48 645 (C36H53O10), 351 (C12H15O12), 289 (C11H13O9), 193 (C6H9O7)
M7-1 Loss of C12H16O13 C30H46O3 453.336 5 -2.1 23.65 407 (C27H35O3), 405 (C28H37O2), 389 (C28H37O), 371 (C24H35O3)
M7-2 Loss of C12H16O12 and oxidation C30H46O5 485.326 1 -2.4 26.93 467 (C29H39O5), 371 (C25H39O2), 291 (C17H23O4), 213 (C12H21O3)
)], attaches=null, journal=Journal(id=1189982048455397383, delFlag=0, nameCn=药学学报, nameEn=Acta Pharmaceutica Sinica, nameHistory1=null, nameHistory2=null, issn=0513-4870, eissn=null, cn=11-2163/R, coden=null, periodic=0, language=CN, oaType=null, ccby=null, superviseOffice=null, ownerOffice=null, pubOffice=null, editorOffice=null, officeType=null, aims=null, clcCode=null, officeProv=null, officeCity=null, officeAddr=null, officeZip=null, officeEmail=null, officePhone=null, editDirector=null, officeDirector=null, officeDirectorPhone=null, officeStaffNum=null, officeEmpNum=null, coverPicUrl=BTxjudbJDVO4PqdBR6On6Q==, journalPrice=null, startedYear=null, abbrevIsoEn=null, journalRemark=null, publicationField=null, createdTime=1761643429151, updatedTime=1761735768113, createdBy=18614031015, updatedBy=13701087609, firstLetterCn=A, firstLetterEn=A, subjectCode=Life Sciences, subjectName=Life Sciences, subjectCodeEn=Life Sciences, subjectNameEn=null, picCn=BTxjudbJDVO4PqdBR6On6Q==, picEn=c4l1ckL55nWbhl1KrFdWIA==, jcr=null, cjcr=null, exts=[JournalExt(id=1190369346338783397, language=CN, name=药学学报, nameHistory1=null, nameHistory2=null, managedBy=, sponsoredBy=, publishedBy=, editorOffice=, officeProv=null, officeCity=null, officeAddr=, officeZip=, editDirector=, officeDirector=null, officePhone=null, coverPicUrl=null, journalRemark=, submitArticleUrl=null, websiteUrl=, createdTime=1761735768160, updatedTime=1761735768160, createdBy=13701087609, updatedBy=13701087609, submissionGuidelinesUrl=, submissionAuthorUrl=https://www.yxxb.com.cn/journalx_yxxb/authorLogOn.action, submissionEditorUrl=https://www.yxxb.com.cn/journalx_yxxb/editorLogOn.action, submissionReviewUrl=https://www.yxxb.com.cn/journalx_yxxb/expertLogOn.action, submissionCeEditorUrl=, submissionAeEditorUrl=, option={"copyright":""}), JournalExt(id=1190369346376532134, language=EN, name=Acta Pharmaceutica Sinica, nameHistory1=null, nameHistory2=null, managedBy=, sponsoredBy=, publishedBy=, editorOffice=, officeProv=null, officeCity=null, officeAddr=, officeZip=, editDirector=, officeDirector=null, officePhone=null, coverPicUrl=null, journalRemark=, submitArticleUrl=null, websiteUrl=, createdTime=1761735768169, updatedTime=1761735768169, createdBy=13701087609, updatedBy=13701087609, submissionGuidelinesUrl=, submissionAuthorUrl=https://www.yxxb.com.cn/journalx_yxxb/authorLogOn.action, submissionEditorUrl=https://www.yxxb.com.cn/journalx_yxxb/editorLogOn.action, submissionReviewUrl=https://www.yxxb.com.cn/journalx_yxxb/expertLogOn.action, submissionCeEditorUrl=, submissionAeEditorUrl=, option={"copyright":""})], databaseList=null, tenantJournalId=1189982191388893191, websiteList=[Website(id=1189982271588340489, webName=null, webTitle=null, webDomain=null, webCopyrigh=null, webIpcNo=null, seoTitle=null, seoKeywords=null, seoDescription=null, tenantJournalId=null, journalId=1189982191388893191, journalNameCn=null, journalNameEn=null, grayFlag=null, tenantId=1146029695717560320, platformId=null, journalGroupId=null, journalGroupNameCn=null, journalGroupNameEn=null, type=1, domain=https://castjournals.cast.org.cn/joweb/yxxb/CN, language=CN, createTime=1761643482348, createBy=18614031015, updateTime=1761643498101, updateBy=18614031015, name=药学学报-中文, tplId=1146099689490845704, title=药学学报, delFlag=0, indexPage=/home, props=[WebsiteProps(id=1189982873114448678, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=articleTextType, value=kx, createTime=1761643625763, updateTime=1761643625763, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873093477155, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=banner, value=null, createTime=1761643625758, updateTime=1761643625758, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873135420201, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=grayFlag, value=0, createTime=1761643625768, updateTime=1761643625768, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873085088546, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=logo, value=https://castjournals.cast.org.cn/joweb/yxxb/CN/file/pic?fileId=w+t2v8bJnX5lh3+hRRJcDA==, createTime=1761643625756, updateTime=1761643625756, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873152197419, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=minRunFlag, value=0, createTime=1761643625772, updateTime=1761643625772, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873110254373, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=picServerUrl, value=https://castjournals.cast.org.cn/joweb/yxxb/CN/file/pic, createTime=1761643625762, updateTime=1761643625762, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873143808810, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=silenceFlag, value=0, createTime=1761643625770, updateTime=1761643625770, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873101865764, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=staticResourcePath, value=https://castjournals.cast.org.cn/joweb/cast_kjdb_cn_619/, createTime=1761643625760, updateTime=1761643625760, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873122837287, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=themeColor, value=null, createTime=1761643625765, updateTime=1761643625765, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873127031592, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=themeStyle, value=null, createTime=1761643625766, updateTime=1761643625766, creator=18614031015, updator=18614031015)]), Website(id=1189982271655449355, webName=null, webTitle=null, webDomain=null, webCopyrigh=null, webIpcNo=null, seoTitle=null, seoKeywords=null, seoDescription=null, tenantJournalId=null, journalId=1189982191388893191, journalNameCn=null, journalNameEn=null, grayFlag=null, tenantId=1146029695717560320, platformId=null, journalGroupId=null, journalGroupNameCn=null, journalGroupNameEn=null, type=1, domain=https://castjournals.cast.org.cn/joweb/yxxb/EN, language=EN, createTime=1761643482364, createBy=18614031015, updateTime=1761643514085, updateBy=18614031015, name=药学学报-英文, tplId=1146101810881728533, title=Acta Pharmaceutica Sinica, delFlag=0, indexPage=/home, props=[WebsiteProps(id=1189982903015633534, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=articleTextType, value=kx, createTime=1761643632892, updateTime=1761643632892, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982902990467707, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=banner, value=null, createTime=1761643632886, updateTime=1761643632886, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982903036605057, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=grayFlag, value=0, createTime=1761643632897, updateTime=1761643632897, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982902982079098, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=logo, value=https://castjournals.cast.org.cn/joweb/yxxb/EN/file/pic?fileId=w+t2v8bJnX5lh3+hRRJcDA==, createTime=1761643632884, updateTime=1761643632884, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982903053382275, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=minRunFlag, value=0, createTime=1761643632901, updateTime=1761643632901, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982903007244925, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=picServerUrl, value=https://castjournals.cast.org.cn/joweb/yxxb/EN/file/pic, createTime=1761643632890, updateTime=1761643632890, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982903044993666, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=silenceFlag, value=0, createTime=1761643632899, updateTime=1761643632899, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982902998856316, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=staticResourcePath, value=https://castjournals.cast.org.cn/joweb/cast_kjdb_en_623/, createTime=1761643632888, updateTime=1761643632888, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982903019827839, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=themeColor, value=null, createTime=1761643632893, updateTime=1761643632893, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982903028216448, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=themeStyle, value=null, createTime=1761643632895, updateTime=1761643632895, creator=18614031015, updator=18614031015)])], journalTitle=药学学报, weixinUrl=null, journalUrl=https://www.yxxb.com.cn/aps, iacademicId=null, status=1, seqNo=null, journalTitleEn=Acta Pharmaceutica Sinica, journalPhotoCn=BTxjudbJDVO4PqdBR6On6Q==, journalPhotoEn=c4l1ckL55nWbhl1KrFdWIA==, journalFirstLetter=A, journalRecommend=null, journalNew=null, journalCollection=null, jcrJf=null, cjcrJf=null, jcrJfStr=null, cjcrJfStr=null, submissionFirstDecision=null, sciSubjectClassification=null, casSubjectClassification=null, citeScore=null, totalCitationFrequency=null, icpCode=null, psCode=null, advertisingLicenseCode=null, copyrightInformation=null, country=null, option=, provinceCode=null, provinceName=null, collectFlag=false), detailUrlCn=https://castjournals.cast.org.cn/joweb/yxxb/CN/10.16438/j.0513-4870.2018-0343, detailUrlEn=https://castjournals.cast.org.cn/joweb/yxxb/EN/10.16438/j.0513-4870.2018-0343, pdfUrlCn=https://castjournals.cast.org.cn/joweb/yxxb/CN/PDF/10.16438/j.0513-4870.2018-0343, pdfUrlEn=https://castjournals.cast.org.cn/joweb/yxxb/EN/PDF/10.16438/j.0513-4870.2018-0343, aliStartDate=null, aliEndDate=null, collectionFlag=false, citedCount=null, citedUrl=null, reference=null)
收藏切换
UHPLC-QTOF-MS法分析鉴定止咳宝片在大鼠血浆中的代谢产物
收藏切换
PDF下载
乔湜 1 , 许海山 1 , 石晓伟 2 , 王伟 1 , 李清艳 1, *
药学学报 | 研究论文 2018,53(9): 1536-1544
收起
收藏切换
药学学报 | 研究论文 2018, 53(9): 1536-1544
UHPLC-QTOF-MS法分析鉴定止咳宝片在大鼠血浆中的代谢产物
全屏
乔湜1, 许海山1, 石晓伟2, 王伟1, 李清艳1, *
作者信息
  • 1.中国民用航空局民用航空医学中心 (民航总医院), 北京 100123
  • 2.河北医科大学药学院, 河北 石家庄 050017

通讯作者:

* 李清艳, Tel:86-10-85762630, E-mail:
Identification of major bioactive components and their metabolites in rat plasma after oral administration of Zhikebao tablet by UHPLC-QTOF-MS
Shi QIAO1, Hai-shan XU1, Xiao-wei SHI2, Wei WANG1, Qing-yan LI1, *
Affiliations
  • 1. Civil Aviation Medical Center, Civil Aviation Administration of China(Civil Aviation General Hospital), Beijing 100123, China
  • 2. School of Pharmacy, Hebei Medical University, Shijiazhuang 050017, China
出版时间: 2018-09-12 doi: 10.16438/j.0513-4870.2018-0343
文章导航
收藏切换
摘要
收起

采用UHPLC-QTOF-MS技术分析大鼠灌胃给予止咳宝片后的血浆生物样本。首先，在正、负离子模式下分别全扫描，通过信息依赖采集触发子离子的采集，每一循环采集8个最强峰的二级质谱图。采集时进行，实时多重质量亏损和动态背景扣除。其次，应用Metabolite Pilot 2.0软件对止咳宝片君药罂粟壳，配伍药物甘草中主要化学成分为目标建立分析模型，分析各成分的保留时间、精确分子质量、二级质谱信息，对代谢产物进行解析。鉴定5个阿片类生物碱、甘草苷和甘草酸，及其相关代谢产物31个。5种阿片类生物碱、甘草苷和甘草酸在大鼠体内的代谢途径包括葡萄糖醛酸化、硫酸化、脱甲基化、脱氨基甲基后羧基化、水解等。本文从定性角度对复方中药制剂中主要活性成分的体内代谢开展研究，并与已有单一化学药物代谢途径比较，为进一步阐明止咳宝片或含罂粟壳、甘草类复方中药制剂体内代谢过程提供基础。

止咳宝片  /  罂粟壳  /  UHPLC-QTOF-MS  /  代谢产物  /  阿片类生物碱  /  甘草

An ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) method was established to identify the metabolites in rat plasma after oral administration of Zhikebao tablets. The high-resolution mass spectrometer was operated in positive and negative ion mode, respectively. First, full-scan was applied, which was dependent on a multiple mass defect filter (MMDF) combined with dynamic background subtraction (DBS). These were utilized to trigger the information dependent acquisition (IDA) function in the experiment. For the IDA criteria, the eight most intense candidate ions of per cycle were selected to do a product ion scan. Then Metabolite Pilot 2.0 software was utilized to load data to seek possible metabolites. The analytical models employed by Metabolite pilot 2.0 were established for representative compounds of the Papaveris Pericarpium and licorice in Zhikebao tablet. Finally, metabolites were identified according to accurate mass measurement and retention time. 38 components from the rat plasma after oral administration of the drug have been found, including 5 prototype opium alkaloids, liquiritin, glycyrrhizic acid and 31 relative metabolites. The metabolic transformation of Zhikebao tablet in rats was mainly induced by glucuronidation, sulfation, methylation, amine to carboxylic acid, hydrolysis and so on. In this paper, the metabolites of the main active components of Zhikebao tablet were tentatively identified, and the metabolic pathway was compared with that of single chemical drugs. Moreover, it laid the fundamental elucidation of further metabolism study of Zhikebao tablet or other compound traditional Chinese medicine preparations which containing Papaveris Pericarpium or licorice.

Zhikebao tablet  /  Papaveris Pericarpium  /  UHPLC-QTOF-MS  /  metabolites  /  opium alkaloids  /  licorice
乔湜, 许海山, 石晓伟, 王伟, 李清艳. UHPLC-QTOF-MS法分析鉴定止咳宝片在大鼠血浆中的代谢产物. 药学学报, 2018 , 53 (9) : 1536 -1544 . DOI: 10.16438/j.0513-4870.2018-0343
Shi QIAO, Hai-shan XU, Xiao-wei SHI, Wei WANG, Qing-yan LI. Identification of major bioactive components and their metabolites in rat plasma after oral administration of Zhikebao tablet by UHPLC-QTOF-MS[J]. Acta Pharmaceutica Sinica, 2018 , 53 (9) : 1536 -1544 . DOI: 10.16438/j.0513-4870.2018-0343
正文
收起
止咳宝片由“紫菀、橘红、桔梗、前胡、枳壳、百部、五味子、罂粟壳浸膏、甘草、薄荷素油、氯化铵”等14味中药组成, 具有宣肺祛痰, 止咳平喘的功效。用于外感风寒所致的咳嗽、痰多清稀、咳甚而喘、慢性支气管炎、上呼吸道感染见上述证候者[1]。它于2009年被收录进岭南中药文化遗产, 其组方按照“君臣佐使”配伍, 君药是罂粟壳浸膏, 能够敛肺镇咳, 主治新咳、久咳。罂粟壳是罂粟科植物罂粟(Papaver somniferum L.)的干燥成熟果壳, 主要含有吗啡、可待因、蒂巴因、罂粟碱、那可丁等化学成分, 具有显著的镇痛、镇咳作用, 也是麻醉药品管理品种中唯一的中药饮片[1, 2]。依据国家食品药品监督管理局《含兴奋剂目录所列物质的中药品种名单》 (2008年)共计1 165种中药品种, 其中102种含有罂粟壳, 且常与中药甘草配伍使用。实验室前期也收集部分复方中药制剂, 并进行含量测定, 结果表明止咳宝片中罂粟壳和甘草主要成分的含量差异较小, 质量较为稳定[3], 但并未有大鼠血浆中止咳宝片相关代谢产物研究的报道。
研究复方中药制剂在体内的代谢产物对阐明中药体内药效物质基础和作用机制发挥着重要作用[4, 5]。其代谢物鉴定的主要难点, 一是基质复杂干扰较多; 二是代谢可能受药物之间相互作用的影响。因此, 鉴定此类代谢产物, 可从君药及代表药物着手, 研究其主要化学成分的代谢产物及代谢途径。2015版《中国药典》以吗啡作为止咳宝片质量控制的指标成分。尽管有关吗啡体内代谢的研究已有报道[6, 7], 但由于与单一化学药品体内过程不同, 复方中药制剂中的化学成分可相互影响或转化, 从而影响药物代谢。在我国, 目前复方中药制剂对疾病的治疗, 注重其整体作用优势和特点。因此, 描绘其体内代谢过程, 对揭示其潜在作用机制更有意义。
中药有效成分在生物体内通常发生广泛代谢, 且由于其代谢途径的多样性和复杂性, 以及内源性物质的干扰, 使得中药代谢物鉴定仍然存在很大的技术挑战[7, 8]。高分辨-四级杆串联质谱具有扫描质量范围宽、速度快、灵敏度高等优点, 同时结合后数据处理系统, 可提供母离子及子离子的精确分子质量和元素组成结构信息, 能较为可靠地快速鉴定复杂生物基质中的代谢产物[8-13]。本文采用UHPLC-QTOF/MS技术对大鼠灌胃给予止咳宝片后血浆中君药(罂粟壳)和甘草中主要化学成分的代谢产物进行鉴定, 推测可能的代谢物结构, 共鉴定罂粟壳中5种阿片类生物碱, 甘草主要成分甘草苷和甘草酸的相关代谢产物31个, 并对比阿片类生物碱作为化学药品的代谢产物类型及途径的不同, 为深入探讨复方中药制剂有效成分之间的相互作用机制以及止咳宝片体内生物过程提供研究基础。
材料与方法
收起
药品和试剂 甲醇(色谱纯, 美国Fisher公司); 甲酸(色谱纯, 德国Sigma公司); 超纯水(美国Millipore公司); 止咳宝片, 批号: 20150915 (广东台城制药股份有限公司)。
仪器 TripleTOF™ 5600型高分辨串联质谱仪(美国AB SCIEX公司); Shimadzu液相色谱系统, 配有LC-30AD二元泵; 在线脱气机、SIL-30AC自动进样器; CTO-30A柱温箱(日本Shimadzu公司); Analyst 1.7和Metabolite Pilot 1.5数据采集、分析软件(美国AB SCIEX公司); 3-18K型台式离心机(德国Sigma公司); MIX-25P型漩涡混合器(杭州米欧仪器有限公司)。
实验动物 雄性SD大鼠4只(体重220~250 g)分成2组, 由北京大学实验动物中心提供, 室温饲养, 自由摄食饮水。于实验前12 h禁食不禁水。给药组(3只)给予粉碎后的止咳宝片羧甲基纤维素钠(CMC-Na)溶液(0.5 g·mL-1), 每只灌胃量2 mL。空白组灌胃给予等量的CMC-Na溶液。
血浆样品的采集及制备 末次给药后0.5、1、2、4、8、12和24 h分别由眼眶静脉丛取血, 每次约0.5 mL, 将血样收集于肝素化的EP管中, 5 000 r·min-1离心5 min, 取上清血浆转移, 将各个采血点血浆样本合并, 置于-80 ℃保存。取大鼠空白血浆及给药血浆各1.0 mL, 甲醇-乙腈(1:1) 3.0 mL沉淀蛋白, 涡旋3 min, 4 ℃、13 000 r·min-1离心10 min, 取上清液, 40 ℃氮气流吹干, 残渣用甲醇300 μL复溶, 超声1 min, 后于4 ℃、13 000 r·min-1离心10 min, 取上清液, 进样5 μL供UHPLC分析。
色谱条件 色谱柱为Acquity UPLC® HSS C18 (2.1 mm × 150 mm, 1.8 μm; Waters, USA); 流动相为甲醇(A)和0.01%甲酸-水(B), 梯度洗脱: 0~20 min, 5%~40% A; 20~30 min, 40%~65% A; 30~35 min, 65%~95% A; 35~40 min, 95% A。流速0.5 mL·min-1, 进样量5.0 μL, 柱温35 ℃。
质谱条件 离子源:电喷雾离子化源, 正、负离子模式分别监测; 离子喷射电压: ± 4 500 V; 源内温度: 600 ℃; 源内气体1 (GS1, N2)和气体2 (GS2, N2)压力: 50 psi (1 psi ≈ 6.9 kPa); 气帘气体(N2)压力: 30 psi。高分辨质谱扫描模式: TOF-MS-IDA-4MS/MS, 扫描质量范围: 100~1 000 amu, 高分辨质谱全扫描的累积时间: 250 ms, MS/MS的累计时间: 100 ms。解簇电压分别为60、-80 V; CE电压为30 eV, CES为15 V。IDA的设置: MMDF (real time multiple mass defect filter)和DBS (dynamic background subtraction)。
数据处理 应用Metabolite Pilot 2.0软件进行数据处理。该软件由AB Sciex公司开发用于寻找和鉴定单体药物代谢物的软件。具有综合预测代谢物、一般峰发现、质量亏损、同位素类型、特征子离子和特征中性丢失等6种功能, 从而能够从复杂基质如生物样品的数据中寻找药物相关化合物。本研究以君药中典型化合物为研究基础, 建立相应化合物鉴定模板, 根据全扫描测得的精确相对分子质量, 在规定误差范围内(± 5.0 ppm), 计算可能的元素组成, 并对比母药的子离子信息及文献报道的数据, 对各色谱峰进行定性分析。
代谢产物鉴定 ①利用高分辨质谱采集的准确分子质量(正、负离子模式下其准分子离子峰分别为[M+H]+和[M-H]-)、同位素峰形、误差值, 进行初步判断。②代谢产物因与母药质谱信息很相似, 在相同质谱条件下存在类似裂解规律, 可能出现相似的子离子, 结合代谢产物子离子扫描信息进行推断。③依据罂粟壳和甘草中主要化学成分(吗啡、可待因、蒂巴因、罂粟碱、那可丁、甘草素和甘草酸)为模板, 应用Metabolite Pilot 2.0建立相应的代谢物筛查模型, 结合其预测代谢物、一般峰发现、质量亏损、同位素类型、特征子离子和特征中性丢失功能进行代谢产物鉴定。
结果
收起
鉴定出大鼠灌胃给予止咳宝片后38个化合物, 代谢产物结果见表 1, 包括吗啡、可待因相关代谢产物共13个、蒂巴因相关代谢产物6个、罂粟碱相关代谢产物4个、那可丁相关代谢产物4个、甘草素相关代谢产物8个和甘草酸相关代谢产物3个。
1 吗啡、可待因及其相关代谢产物
吗啡(M1)的保留时间为4.32 min, 准分子离子峰为([M+H]+m/z 286.145 1), 特征性碎片为m/z 229 (C14H13O3=C17H19NO3-C3H7N), 与之对应的为哌啶环的断裂及N-甲基的丢失(C3H7N, 57 Da), 哌啶环断裂后进一步丢失CO或H2O, 产生一系列子离子分别为m/z 211 (C14H11O2=C14H13O3-H2O)、201 (C13H13O2= C14H13O3-CO)、185 (C12H9O2=C14H13O3-C2H4O)和165 (C13H9)[14]。可待因(M1)为3-甲基化吗啡, 与吗啡具有相似的代谢途径, 其二级质谱图的子离子主要为m/z 282 (C18H20NO2)、243 (C15H17NO2)、225 (C15H13O2)、215 (C14H15O2)、199 (C13H11O2)、165 (C13H9)。
共鉴定出吗啡相关代谢产物10个, 7个Ⅰ相代谢产物、3个Ⅱ相代谢产物, 代谢产物总离子流图和代谢途径见图 1。化合物M1-1和M1-2的准分子离子为m/z 462.175 7, 保留时间分别为2.25 min和3.11 min, 较吗啡多176 Da, 其子离子m/z 229、211为吗啡的特征子离子, 推断M1-1和M1-2为吗啡的葡萄糖醛酸化代谢产物, 经与文献比较[6, 7], M1-1和M1-2分别为吗啡-3-葡萄糖醛酸和吗啡-6-葡萄糖醛酸代谢产物。M1-6的准分子离子峰为m/z 446.182 4 ([M+H]+, C23H27NO8), 保留时间为15.47 min, 其准分子离子峰与M1-1和M1-2相差16 Da, 推断其为吗啡丢氧后葡萄糖醛酸化代谢产物。M1-3的保留时间为7.57 min, 准分子离子峰为m/z 258.111 5 ([M+H]+, C15H17NO3), 特征子离子m/z 240、184推断为丢失N-甲基后, 哌啶环断裂的代谢产物。M1-4的保留时间为8.19 min, 准分子离子峰为m/z 366.109 8 ([M+H]+, C17H20NO6P), 比吗啡的高80 Da (PO3H), 为其磷酸化代谢产物。M1-5的保留时间为9.51 min, 准分子离子峰为m/z 328.156 0 ([M+H]+, C19H21NO4), 较吗啡多43 Da (COCH3), 子离子为m/z 237、165, 为其N-乙酰化的代谢产物。吗啡哌啶环上的N-甲基易于丢失后形成羧基, M1-7~M1-10为其N-甲基转化为羧基的代谢产物。M1-8的保留时间为23.35 min, 准分子离子峰为m/z 315.122 4 ([M+H]+, C18H18O5), 子离子为m/z 279、123、107, 为吗啡丢失N-甲基后羧酸化代谢产物。M1-7和M1-10的保留时间分别为21.91 min和27.92 min, 准分子离子峰为m/z 299.126 4 ([M+H]+, C18H18O4), 较M1-8少16 Da, 为吗啡丢失O和N-甲基后羧酸化代谢产物。M1-9保留时间为24.95 min, 准分子离子峰为m/z 283.132 0 ([M+H]+, C18H18O3)较M1-8少32 Da, 吗啡丢失2O和N-甲基后羧酸化代谢产物。代谢产物详细信息见表 1。
可待因与吗啡结果相似, 在体内两者可以相互转化, 以可待因为母药监测的绝大多数代谢产物, 同样在吗啡为母药的代谢物监测中。M2-1的准分子离子峰为m/z 301.142 6 ([M+H]+, C18H20O4), 保留时间为34.62 min, 推测其为N-甲基丢失后变为醇的代谢产物。
2 蒂巴因及其相关代谢产物
蒂巴因(M3)的保留时间为12.89 min, 准分子离子峰为([M+H]+m/z 312.158 9), 特征性碎片为m/z 281 (C18H17O3)、266 (C16H21NO3)、58 (C3H8N)。共鉴定出蒂巴因(M3)相关代谢产物5个, 2个Ⅰ相代谢产物、3个Ⅱ相代谢产物, 总离子流图和代谢途径见图 2。
M3-1和M3-2的准分子离子峰为m/z 474.177 0 ([M+H]+, C24H27NO9), 保留时间分别为5.37 min和6.32 min, 较蒂巴因多162 Da (M-CH2+Glu), 为其丢失CH2后葡萄糖醛酸化代谢产物。M3-4的准分子离子峰为m/z 392.115 2 ([M+H]+, C19H21NO6S), 保留时间为31.39 min, 其准分子离子峰与M3相差80 Da (SO3), 子离子为m/z 332、274、246, 推断为其硫酸化代谢产物。蒂巴因同样存在丢失N-甲基后羧酸化的代谢产物(M3-3和M3-5)。M3-3的保留时间为9.49 min, 准分子离子峰为m/z 297.113 6 ([M+H]+, C18H16O4), 子离子为237 (C16H13O2)、222 (C15H10O2)、205 (C15H9O)、189 (C11H9O3), 为蒂巴因丢失2CH2和N-甲基后羧酸化代谢产物。M3-5的保留时间为36.19 min, 准分子离子峰为m/z 327.124 0 ([M+H]+, C19H18O5), 子离子为m/z 227 (C14H11O3)、121 (C7H5O2), 为蒂巴因丢失CH2和N-甲基后羧酸化代谢产物。
3 罂粟碱及其相关代谢产物
罂粟碱(M4)的保留时间为15.04 min, 准分子离子峰为([M+H]+m/z 340.153 7), 特征性碎片为m/z 324 (C18H17O3)、202 (C12H12NO2)、187 (C12H13NO)、171 (C11H9NO)、156 (C10H6NO)。共鉴定出M4相关代谢产物3个, 2个Ⅰ相代谢产物、1个Ⅱ相代谢产物。代谢产物总离子流图和代谢途径见图 3。
M4-1的准分子离子峰为m/z 278.116 3 ([M+H]+, C18H15NO2), 保留时间为3.11 min, 子离子为m/z 215 (C16H9N)、144 (C10H10N)、142 (C10H8N)、130 (C9H8N), 推断为丢失2个甲氧基后, 另外两个甲氧基形成的桥环代谢产物。M4-2的准分子离子峰为m/z 474.175 6 ([M+H]+, C24H27NO9), 保留时间为6.32 min, 子离子为m/z 327 (C19H21NO4)、284 (C17H18NO3)、249 (C16H11NO2), 推断为丢失2CH2后加和葡萄糖的代谢产物。M4-3的准分子离子峰为m/z 328.156 0 ([M+H]+, C19H21NO4), 保留时间为9.51 min, 子离子为m/z 297 (C17H15NO4)、282(C16H12NO4)、265 (C16H11NO3), 推断为丢失CH2O后水和的代谢产物。
4 那可丁及其相关代谢产物
那可丁(M5)的保留时间为15.20 min, 准分子离子峰为([M+H]+ m/z 414.155 7), 子离子为m/z 353 (C20H19NO5)、220 (C12H14NO3)、205 (C11H11NO3)、175(C11H13NO)。共鉴定出M5相关代谢产物3个Ⅰ相代谢产物。代谢产物总离子流图和代谢途径见图 4。
那可丁的3个Ⅰ相代谢产物, 为丢失N-甲基后羧酸化代谢产物。M5-3的准分子离子峰为m/z 442.131 6 ([M+H]+, C23H22O9), 保留时间为16.95 min, 较M5多28 Da (COOH-NH3), 子离子为m/z 267 (C13H15O6)、199 (C12H7O), 推断为M5丢失N-甲基后羧酸化代谢产物。M5-1和M5-2的准分子离子峰为m/z 382.114 2 ([M+H]+, C21H18O7), 保留时间分别为14.62和14.84 min, 较M5-3少60 Da (2CH2O), 子离子为m/z 308 (C19H16O4)、201 (C12H19O3)、188 (C11H8O3), 推断其为M5-3丢失2CH2O后的代谢产物。
5 甘草苷及其相关代谢产物
甘草苷(M6)的保留时间为14.81 min, 准分子离子峰为([M-H]- m/z 417.117 1), 子离子为m/z 255 (C15H11O4)、241 (C15H13O3)、135 (C8H7O2)、121 (C7H5O2)。共鉴定出M6相关代谢产物7, 其中Ⅰ相代谢产物6个, Ⅱ相代谢产物1个。代谢产物总离子流图和代谢途径见图 5。
甘草苷结构中含有1分子葡萄糖, 在体内易于丢失葡萄糖而水解形成苷元[16]。代谢产物M6-3和M6-6准分子离子峰为m/z 255.065 8 ([M-H]-, C15H12O4), 保留时间分别为17.95和23.33 min, 较M6少162 Da, 与文献[15]报道一致, 为其水解葡萄糖的代谢产物。M6-1的准分子离子峰为m/z 497.074 0 ([M-H]-, C21H22O12S), 保留时间为31.39 min, 其准分子离子峰与M6相差80 Da (SO3), 特征子离子为m/z 417、241, 与M6的子离子一致, 推断为其硫酸化代谢产物。M6-2的准分子离子峰为m/z 419.132 9 ([M-H]-, C21H24O9), 保留时间为16.92 min, 其准分子离子峰较M6多2 Da, 特征子离子为m/z 243, 也较M6多2 Da, 推测其为M6的氢化代谢产物。M6-4的准分子离子峰为m/z 467.117 2 ([M-H]-, C21H24O12), 保留时间为19.35 min, 较M6多50 Da (2O和H2O), 子离子为m/z 421 (C20H21O10)、399 (C18H23O10)、256 (C15H12O4), 推断为M6双氧化后水合的代谢产物。M6-5的准分子离子峰为m/z 385.128 5 ([M-H]-, C21H22O7), 保留时间为22.85 min, 较M6少32 Da (2O), 子离子为249 (C17H13O2)、119 (C8H7O), 推断为M6丢失2O的代谢产物。M6-7的准分子离子峰为m/z 399.145 3 ([M-H]-, C22H24O7), 保留时间为25.10 min, 较M6-5多14 Da, 子离子为217 (C16H9O)、163 (C6H11O5), 推断为M6丢失2O后甲基化的代谢产物。
6 甘草酸及其相关代谢产物
甘草酸(M7)的保留时间为24.48 min, 准分子离子峰为([M-H]- m/z 821.393 7), 子离子为m/z 645 (C36H53O10)、351 (C12H15O12)、289 (C11H13O9)、193 (C6H9O7)。共鉴定出M7相关代谢产物2个(I相代谢产物)。代谢产物总离子流图和代谢途径见图 6。
甘草酸为五环三萜类化合物, 其分子结构中含一分子甘草次酸和两分子葡萄糖醛酸组成, 在体内易于丢失2分子葡萄糖醛酸而水解形成甘草次酸[15]。代谢产物M7-1, 准分子离子峰为m/z 453.336 5 ([M-H]-, C30H46O3), 保留时间为23.65 min, 较M7少368 Da, 子离子为407 (C27H35O3)、405 (C28H37O2)、389 (C28H37O)、371(C24H35O3), 为其水解两分子葡萄糖醛酸丢失O的代谢产物。M7-2的准分子离子峰为m/z 485.326 1 ([M-H]-, C30H46O5), 保留时间为26.93 min, 较M7-1多32 Da, 子离子为467 (C29H39O5)、371 (C25H39O2)、291 (C17H23O4)、213 (C12H21O3), 为M7水解两分子葡萄糖醛酸加O的代谢产物。
讨论
收起
本研究利用UHPLC-QTOF-MS/MS技术鉴定了罂粟壳、甘草中5种生物碱、甘草素和甘草酸在大鼠体内的31个代谢产物。结果表明, 5种生物碱、甘草素和甘草酸在大鼠体内的代谢途径包括葡萄糖醛酸化、硫酸化、脱甲基化、脱氨基甲基后羧基化、葡萄糖水解等。
吗啡和可待因在结构上类似, 仅在C-3位相差一个CH3, 因此在鉴定结果中上述两种化合物的代谢产物有重叠。文献[7, 8]已有报道吗啡体内代谢产物主要有吗啡-3-葡萄糖醛酸(M1-1)、吗啡-6-葡萄糖醛酸(M1-2)、N-去甲基代谢产物, 其中M1-1代谢产物含量大于M1-2, 这与文献报道一致[8]。大鼠灌胃给予止咳宝片后, 血浆中除葡萄糖醛酸化代谢产物外, 还发现主要代谢产物类型为丢失N-甲基后变成羧酸代谢产物, 并未发现N-去甲基代谢产物, 推测N-去甲基吗啡可能为代谢产物的中间体, 后在体内转化为羧基, 其次可能与复方中药制剂的多成份体内相互作用有关。
在正离子扫描模式下(5种阿片类生物碱)鉴定的22个代谢产物中有9个代谢产物为丢失N-甲基后形成羧酸的代谢产物, 含有N-甲基的阿片类生物碱(吗啡、蒂巴因、那可丁)易形成此类化合物, 这在阿片类体内代谢产物鉴定的研究中罕有报道。阿片类生物碱在结构中含有甲氧基, 其中可待因含有1个OCH3, 蒂巴因含有2个OCH3, 那可丁含有3个OCH3, 罂粟碱含有4个OCH3。鉴定的代谢结果显示, 代谢产物易于丢失甲氧基后在进一步与葡萄糖醛酸等结合形成极性大的Ⅱ相代谢产物。大鼠血浆中阿片类生物碱体内主要以Ⅰ相代谢物为主, Ⅱ相代谢产物以葡萄糖醛酸化代谢产物为主。在负离子扫描模式下, 甘草的特征成分以甘草苷和甘草酸为主, 共鉴定出9个代谢产物, 主要为葡萄糖苷水解的代谢产物, 甘草苷可水解一份子葡萄糖(M6-3和M6-6)形成苷元[15], 甘草酸的代谢产物为丢失2分子葡萄糖醛酸后再进行氧化、去氧化的代谢产物。甘草苷在大鼠血浆中的Ⅱ相代谢以硫酸化为主。
结果表明, 复方中药制剂中代谢产物与单一化学药物体内代谢产物的种类有一定区别[16]。中药有效成分在生物体内通常发生广泛代谢, 复方中药制剂药味繁多, 有效成分既可以在体内发生相互转化, 也可影响其他成分的代谢。因此, 应进一步对其作用机制进行深入分析, 以全面阐明止咳宝片或含罂粟壳、甘草类复方中药制剂的药体内代谢过程。
基金
收起
  • 民航安全能力建设基金资助项目(DFS20160604)
文献
收起
参考文献 引证文献
排序方式：
[1]
Chinese Pharmacopoeia Commission. Pharmacopoeia of the People's Republic of China (中华人民共和国药典)[S]. Vol 1. 2015 ed. Beijing: China Medical Science Press, 2015: 624.
[2]
Chen M. Clinical application and management of Papaver somniferum[J]. China Pharm (中国药房), 2016, 27: 3461-3463.
[3]
Liu GR, Qiao S, Liu TB, et al. Simultaneous determination of 18 chemical constituents in traditional Chinese medicine of antitussive by UPLC-MS-MS[J]. J Chromatogr Sci, 2016, 54: bmw099.
[4]
Geng JL, Dai Y, Yao ZH, et al. Metabolites profile of Xian-Ling-Gu-Bao capsule, a traditional Chinese medicine prescription, in rats by ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry analysis[J]. J Pharm Biomed Anal, 2014, 96: 90-103.
[5]
Zheng C, Hao H, Wang X, et al. Diagnostic fragmention-based extension strategy for rapid screening and identification of serial components of homologous families contained in traditional Chinese medicine prescription using high-resolution LC-ESI-IT-TOF/MS: Shengmai injection as an example[J]. J Mass Spectrom, 2009, 44: 230-244.
[6]
Bosch ME, Sánchez AR, Rojas FS, et al. Morphine and its metabolites: analytical methodologies for its determination[J]. J Pharm Biomed Anal, 2007, 43: 799-815.
[7]
Liu YZ. Metabolism of morphine in vivo[J]. Heilongjiang Med J (黑龙江医药), 2010, 23: 252-253.
[8]
Li L, Chen XY, Zhong DF. Applications of liquid chromatography-mass spectrometry in drug metabolite identification[J]. J Chin Mass Spectrom Soc (质谱学报), 2017, 38: 375-387.
[9]
Wang YX, Hao HP, Wang GJ. Application of Q-TOF and IT-TOF mass spectrometry technology in identifying the natural products and the biological metabolites[J]. Chin J Nat Med, 2009, 7: 394-400.
[10]
Wang N, Hassan H, Jia YM, et al. Identification of polygala oligosaccharide esters and their metabolites in rat plasma after oral administration of ethanol extract of Kai Xin San by UHPLC-MS[J]. Acta Pharm Sin (药学学报), 2017, 52: 1592-1598.
[11]
Cheng YX, Chen LJ, Wang ZM, et al. Analysis of major bioactive components and their metabolites in rats' plasma, urine and feces after oral administration of the aqueous extract of Euodiae Fructus by UHPLC-QTOF-MS[J]. Acta Pharm Sin (药学学报), 2017, 52: 1157-1164.
[12]
Su LL, Cheng X, Ji D, et al. Analysis of lignans and their metabolites derived from Schisandra chinensis and vinegar Schisandra chinensis in rats' plasma, bile, urine and faeces based on UHPLC-QTOF/MS[J]. Acta Pharm Sin (药学学报), 2016, 51: 1600-1608.
[13]
Li J, Hua ZD, Wang YM. Analysis of metabolites and metabolic pathway of 5F-AMB in vitro using UPLC-HR-MS[J]. Acta Pharm Sin (药学学报), 2017, 52: 1743-1747.
[14]
Zhang Z, Yan B, Liu K, et al. Fragmentation pathways of heroin-related alkaloids revealed by ion trap and quadrupole time-of-flight tandem mass spectrometry [J]. Rapid Commun Mass Spectrom, 2008, 22: 2851-2862.
[15]
Xiang C, Qiao X, Wang Q, et al. From single compounds to herbal extract: a strategy to systematically characterize the metabolites of licorice in rats [J]. Drug Metab Dispos, 2011, 39: 1597-1608.
[16]
Xie PS, Leung AY. Understanding the traditional aspect of Chinese medicine in order to achieve meaningful quality control of Chinese materia medica[J]. J Chromatogr A, 2009, 1216: 1933-1940.
2018年第53卷第9期
PDF下载
189
75
引用本文
BibTeX
文章信息
doi: 10.16438/j.0513-4870.2018-0343
  • 接收时间：2018-05-13
  • 首发时间：2026-01-15
  • 出版时间：2018-09-12
补充材料
相关文章
文章信息
作者
出版历史
  • 收稿日期：2018-05-13
  • 修回日期：2018-07-17
基金
民航安全能力建设基金资助项目(DFS20160604)
作者信息
    1.中国民用航空局民用航空医学中心 (民航总医院), 北京 100123
    2.河北医科大学药学院, 河北 石家庄 050017

通讯作者:

* 李清艳, Tel:86-10-85762630, E-mail:
参考文献
分享链接
https://castjournals.cast.org.cn/joweb/yxxb/CN/10.16438/j.0513-4870.2018-0343
分享至
全文二维码

扫描看全文

引用本文
BibTeX
本文的引用情况
2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
关闭全屏
相关链接
论文
最新文章
热读文章
热点专题
内参
蓝皮书
产业发展报告
传播力报告
期刊分级目录
资讯
学术新闻
行业新闻
学术会议
行业会议
关于
关于我们
联系我们
北京市海淀区学院南路86号
100081
010-62199257
qkjq@cast.org.cn

中国科学技术协会版权所有 京ICP 备10216604号-4 海淀分局备案 1101084647
科技导报社主办 中国科协信息中心技术支持