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Article(id=1195386782939394293, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1195386781278449897, articleNumber=1001-2494(2024)01-0078-10, orderNo=null, doi=10.11669/cpj.2024.01.010, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1685376000000, receivedDateStr=2023-05-30, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1762932018265, onlineDateStr=2025-11-12, pubDate=1704643200000, pubDateStr=2024-01-08, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1762932018265, onlineIssueDateStr=2025-11-12, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1762932018265, creator=13701087609, updateTime=1762932018265, updator=13701087609, issue=Issue{id=1195386781278449897, tenantId=1146029695717560320, journalId=1190317699101192196, year='2024', volume='59', issue='1', pageStart='1', pageEnd='96', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1762932017868, creator=13701087609, updateTime=1762998488032, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1195665577399333609, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1195386781278449897, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1195665577399333610, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1195386781278449897, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=78, endPage=87, ext={EN=ArticleExt(id=1195386783170081016, articleId=1195386782939394293, tenantId=1146029695717560320, journalId=1190317699101192196, language=EN, title=Impurity Profile Study of Tacrolimus Ointment Based on High Performance Liquid Chromatography-High Resolution Mass Spectrometry, columnId=null, journalTitle=Chinese Pharmaceutical Journal, columnName=null, runingTitle=null, highlight=null, articleAbstract=

OBJECTIVE To investigate the impurity profile of tacrolimus ointment and lay a foundation for the establishment of generic drug quality standard. METHODS HPLC-HRMS/MS was adopted to analyze the impurities in destroyed tacrolimus ointment. According to the primary and secondary mass spectrometry data combined with the mass spectrometry fragmentation patterns of impurities, the source and molecular structures of the impurities were speculated. RESULTS Tacrolimus ointment totally produced 10 impurities after destructive test, wherein contained three groups of isomers. CONCLUSION The analysis method of impurity profile established in this study provides a reference basis for the quality control and process optimization of tacrolimus ointment.

, correspAuthors=BAI Wenming, authorNote=null, correspAuthorsNote=null, copyrightStatement=null, 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=BU Ren, ZHOU Gang, SHENG Hua, LIAN Hua, CAO Huimin, ZHU Zhaozhen, BAI Wenming), CN=ArticleExt(id=1195387307894289041, articleId=1195386782939394293, tenantId=1146029695717560320, journalId=1190317699101192196, language=CN, title=基于高效液相色谱-高分辨串联质谱的他克莫司软膏杂质谱研究, columnId=1190352405612040510, journalTitle=中国药学杂志, columnName=论著, runingTitle=null, highlight=null, articleAbstract=

目的 研究他克莫司软膏的杂质谱,为仿制药质量标准制定提供依据。方法 采用高效液相色谱-高分辨串联质谱联用技术分析强制破坏后的他克莫司软膏杂质,根据一级、二级质谱数据结合杂质的质谱裂解方式,推测各杂质的来源和分子结构。结果 他克莫司软膏强制破坏后,共产生10个杂质,其中包括3组同分异构体。 结论 本研究建立的杂质谱分析方法为他克莫司软膏的质量控制和工艺优化提供了参考依据。

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*白文明,男,博士,副教授 研究方向:药效物质基础与药物质量控制研究 Tel:(0471)6653144
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布仁,男,本科,副教授 研究方向:药效物质基础与药物质量控制研究

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布仁,男,本科,副教授 研究方向:药效物质基础与药物质量控制研究

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布仁,男,本科,副教授 研究方向:药效物质基础与药物质量控制研究

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keyword=高效液相色谱-高分辨串联色谱)], refs=[Reference(id=1195498849168048967, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195386782939394293, doi=null, pmid=null, pmcid=null, year=2023, volume=39, issue=8, pageStart=3095, pageEnd=3110, url=null, language=null, rfNumber=[1], rfOrder=0, authorNames=JIN L Q, LU D, LIU Z, journalName=生物工程学报, refType=null, unstructuredReference=JIN L Q, LU D, LIU Z, et al. Biosynthesis of immunosuppressant tacrolimus:a review[J]. Chin J Biotechnol(生物工程学报), 2023, 39(8):3095-3110. DOI: 10.13345/j.cjb.220994., articleTitle=Biosynthesis of immunosuppressant tacrolimus:a review, refAbstract=null), Reference(id=1195498849235157832, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195386782939394293, doi=null, pmid=null, pmcid=null, year=2003, volume=24, issue=5, pageStart=274, pageEnd=277, url=null, language=null, rfNumber=[2], rfOrder=1, authorNames=CHEN L Z, WANG C X, QIU J, journalName=中华器官移植杂质, refType=null, unstructuredReference=CHEN L Z, WANG C X, QIU J, et al. A comparison of long-term effect and safety between tactolimus and cyclosporine in cdaveric renal transplantation[J]. Chin J Organ Transplant(中华器官移植杂质), 2003, 24(5):274-277., articleTitle=A comparison of long-term effect and safety between tactolimus and cyclosporine in cdaveric renal transplantation, refAbstract=null), Reference(id=1195498849293878089, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195386782939394293, doi=null, pmid=null, pmcid=null, year=2018, volume=7, issue=1, pageStart=9, pageEnd=21, url=null, language=null, rfNumber=[3], rfOrder=2, authorNames=KROPEIT D, von RICHTER O, STOBERNACK H P, journalName=Clin Pharmacol Drug Dev, refType=null, unstructuredReference=KROPEIT D, von RICHTER O, STOBERNACK H P, et al. Pharmacokinetics and safety of letermovir coadministered with cyclosporine A or tacrolimus in healthy subjects[J]. Clin Pharmacol Drug Dev, 2018, 7(1):9-21., articleTitle=Pharmacokinetics and safety of letermovir coadministered with cyclosporine A or tacrolimus in healthy subjects, refAbstract=null), Reference(id=1195498849360986954, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195386782939394293, doi=null, pmid=null, pmcid=null, year=2023, volume=14, issue=2, pageStart=257, pageEnd=264, url=null, language=null, rfNumber=[4], rfOrder=3, authorNames=ZOU Z Y, CHEN S, ZHANG W J, journalName=器官移植, refType=null, unstructuredReference=ZOU Z Y, CHEN S, ZHANG W J, et al. Early application of tacrolimus extended-release capsule after kidney transplantation[J]. Organ Transplant(器官移植), 2023, 14(2):257-264., articleTitle=Early application of tacrolimus extended-release capsule after kidney transplantation, refAbstract=null), Reference(id=1195498849436484427, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195386782939394293, doi=null, pmid=null, pmcid=null, year=2018, volume=19, issue=4, pageStart=342, pageEnd=350, url=null, language=null, rfNumber=[5], rfOrder=4, authorNames=SCHUTTE-NUTGEN K, THOLKING G, SUWELACK B, journalName=Curr Drug Metab, refType=null, unstructuredReference=SCHUTTE-NUTGEN K, THOLKING G, SUWELACK B, et al. Tacrolimus pharmacokinetic considerations for clinicians[J]. Curr Drug Metab, 2018, 19(4):342-350., articleTitle=Tacrolimus pharmacokinetic considerations for clinicians, refAbstract=null), Reference(id=1195498849507787596, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195386782939394293, doi=null, pmid=null, pmcid=null, year=2022, volume=38, issue=24, pageStart=3145, pageEnd=3149, url=null, language=null, rfNumber=[6], rfOrder=5, authorNames=WANG Z Z, ZHENG H, YANG B, journalName=J Pract Med, refType=null, unstructuredReference=WANG Z Z, ZHENG H, YANG B, et al. Correlation between intra-individual variability of tacrolimus and the prognosis of heart transplantation[J]. J Pract Med (实用医学杂志), 2022, 38(24):3145-3149., articleTitle=Correlation between intra-individual variability of tacrolimus and the prognosis of heart transplantation, refAbstract=null), Reference(id=1195498849579090765, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195386782939394293, doi=null, pmid=null, pmcid=null, year=2022, volume=42, issue=22, pageStart=2373, pageEnd=2382, url=null, language=null, rfNumber=[7], rfOrder=6, authorNames=YE C, LI J, CHEN P, journalName=中国医院药学杂志, refType=null, unstructuredReference=YE C, LI J, CHEN P, et al. Evaluation of concentration, effectiveness and safety of original and generic tacrolimus in patients at early stage after kidney transplantation[J]. 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A-TIC; B-mass spectrum.

, figureFileSmall=F4gCTmN6ZLACGYzd/vQkhA==, figureFileBig=mytJDYfftLo+/xfvvA8PQA==, tableContent=null), ArticleFig(id=1195498845468672799, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195386782939394293, language=CN, label=图1, caption=他克莫司原料药的总离子流图和质谱图

A-总离子流图;B-质谱图。

, figureFileSmall=F4gCTmN6ZLACGYzd/vQkhA==, figureFileBig=mytJDYfftLo+/xfvvA8PQA==, tableContent=null), ArticleFig(id=1195498845556753184, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195386782939394293, language=EN, label=Fig.2, caption=TIC and mass spectra of tacrolimus test sample after light damage

A-TIC; B-mass spectrum; ①-tacrolimums related compound Ⅵ; ②-tacrolimus related compound Ⅷ; ③-tacrolimus related compound Ⅵ8-epimer.

, figureFileSmall=7aimZsrwH2DcxoVLsEfmxQ==, figureFileBig=VZAjzXye2MVQjGQr2eDhOQ==, tableContent=null), ArticleFig(id=1195498845615473441, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195386782939394293, language=CN, label=图2, caption=光照破坏他克莫司供试品的总离子流图和质谱图

A-总离子流图;B-质谱图;①-他克莫司有关物质Ⅵ;②-他克莫司有关物质Ⅷ; ③-他克莫司有关物质Ⅵ8位差向异构体。

, figureFileSmall=7aimZsrwH2DcxoVLsEfmxQ==, figureFileBig=VZAjzXye2MVQjGQr2eDhOQ==, tableContent=null), ArticleFig(id=1195498845669999394, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195386782939394293, language=EN, label=Fig.3, caption=TIC and mass spectra of tacrolimus test sample after acid damage

A-TIC; B-mass spectrum; ①-tacrolimus 8-epimer; ②-tacrolimus diene.

, figureFileSmall=JXwp5IvQqW36SDTEuCNFnA==, figureFileBig=3Lw3DJAIa7MSQrGEIV9+nQ==, tableContent=null), ArticleFig(id=1195498845741302563, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195386782939394293, language=CN, label=图3, caption=酸破坏他克莫司供试品总离子流图和质谱图

A-总离子流图;B-质谱图;①-他克莫司8位差向异构体;②-他克莫司二烯。

, figureFileSmall=JXwp5IvQqW36SDTEuCNFnA==, figureFileBig=3Lw3DJAIa7MSQrGEIV9+nQ==, tableContent=null), ArticleFig(id=1195498845804217124, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195386782939394293, language=EN, label=Fig.4, caption=TIC and mass spectra of tacrolimus test sample after high temperature damage

A-TIC; B-mass spectrum; ①-tacrolimus lactone isomer; ②-tacrolimus regioisomers; ③-tacrolimus 19-epimer.

, figureFileSmall=cn++ZI7TuDCyOpBxy3BZgg==, figureFileBig=1+xEu12LJ70q5y76tYcHpw==, tableContent=null), ArticleFig(id=1195498845862937381, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195386782939394293, language=CN, label=图4, caption=高温破坏他克莫司供试品总离子流图和质谱图

A-总离子流图;B-质谱图;①-他克莫司内酯异构体;②-他克莫司位置异构体; ③-他克莫司19位差向异构体。

, figureFileSmall=cn++ZI7TuDCyOpBxy3BZgg==, figureFileBig=1+xEu12LJ70q5y76tYcHpw==, tableContent=null), ArticleFig(id=1195498845917463334, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195386782939394293, language=EN, label=Fig.5, caption=TIC and mass spectra of tacrolimus test sample after alkali damage

A-TIC; B-mass spectrum; ①-tacrolimus 8-epimer; ②-tacrolimus open ring.

, figureFileSmall=mpACTAHSTIns1l3VXj3MZA==, figureFileBig=56EpnCO0r0LHrC7jXlg+NA==, tableContent=null), ArticleFig(id=1195498845980377895, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195386782939394293, language=CN, label=图5, caption=碱破坏他克莫司供试品的总离子流图和质谱图

A-总离子流图;B-质谱图;①-他克莫司8位差向异构体;②-他克莫司开环异构体。

, figureFileSmall=mpACTAHSTIns1l3VXj3MZA==, figureFileBig=56EpnCO0r0LHrC7jXlg+NA==, tableContent=null), ArticleFig(id=1195498846047486760, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195386782939394293, language=EN, label=Fig.6, caption=Mass fragmentation pathway of tacrolimus under positive ion mode, figureFileSmall=ZLiwjhzNR46pH9pX2hj46A==, figureFileBig=IgjNLJGfVZPIVCfbFYKEhw==, tableContent=null), ArticleFig(id=1195498846110401321, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195386782939394293, language=CN, label=图6, caption=他克莫司在正离子模式下的质谱裂解方式, figureFileSmall=ZLiwjhzNR46pH9pX2hj46A==, figureFileBig=IgjNLJGfVZPIVCfbFYKEhw==, tableContent=null), ArticleFig(id=1195498846173315882, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195386782939394293, language=EN, label=Fig.7, caption=Mass fragmentation pathway Ⅰ of main fragment ions of tacrolimus under positive ion mode, figureFileSmall=3KZr9y9VBX2OVg276qSyeg==, figureFileBig=atHNHymhFX+LwkYi5jB6Ig==, tableContent=null), ArticleFig(id=1195498846236230443, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195386782939394293, language=CN, label=图7, caption=他克莫司主要碎片离子在正离子模式下的可能裂解方式Ⅰ, figureFileSmall=3KZr9y9VBX2OVg276qSyeg==, figureFileBig=atHNHymhFX+LwkYi5jB6Ig==, tableContent=null), ArticleFig(id=1195498846290756396, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195386782939394293, language=EN, label=Fig.8, caption=Mass fragmentation pathway Ⅱ of main fragment ions of tacrolimus under positive ion mode, figureFileSmall=/vkbVzOVW+FqTfqv6B26Jw==, figureFileBig=sNZjojyJWYZPoBBLf3oIrQ==, tableContent=null), ArticleFig(id=1195498846349476653, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195386782939394293, language=CN, label=图8, caption=他克莫司主要碎片离子在正离子模式下的可能裂解方式Ⅱ, figureFileSmall=/vkbVzOVW+FqTfqv6B26Jw==, figureFileBig=sNZjojyJWYZPoBBLf3oIrQ==, tableContent=null), ArticleFig(id=1195498846404002606, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195386782939394293, language=EN, label=Fig.9, caption=Mass fragmentation pathway Ⅲ of main fragment ions of tacrolimus under positive ion mode, figureFileSmall=qp4a1uaF6FWkWGIYITQFpA==, figureFileBig=oKwyHNg7trfY//iN2UeX3Q==, tableContent=null), ArticleFig(id=1195498846462722863, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195386782939394293, language=CN, label=图9, caption=他克莫司主要碎片离子在正离子模式下的可能裂解方式Ⅲ, figureFileSmall=qp4a1uaF6FWkWGIYITQFpA==, figureFileBig=oKwyHNg7trfY//iN2UeX3Q==, tableContent=null), ArticleFig(id=1195498846517248816, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195386782939394293, language=EN, label=Fig.10, caption=Mass fragmentation pathway Ⅳ of main fragment ions of tacrolimus under positive ion mode, figureFileSmall=USyvJ9PTZNdLDuLyVMaYGA==, figureFileBig=vZcG85QdYxqJULOZaTipTQ==, tableContent=null), ArticleFig(id=1195498846584357681, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195386782939394293, language=CN, label=图10, caption=他克莫司主要碎片离子在正离子模式下的可能裂解方式Ⅳ, figureFileSmall=USyvJ9PTZNdLDuLyVMaYGA==, figureFileBig=vZcG85QdYxqJULOZaTipTQ==, tableContent=null), ArticleFig(id=1195498846647272242, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195386782939394293, language=EN, label=Fig.11, caption=Structure transformation pathway of tacrolimus diene and tacrolimus diene 8-epimer under positive ion mode, figureFileSmall=KcyH/sB5llom962JTzrgKw==, figureFileBig=QFx+DeIKRrJZuhdqHabyzA==, tableContent=null), ArticleFig(id=1195498846710186803, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195386782939394293, language=CN, label=图11, caption=他克莫司二烯和他克莫司二烯8位差向异构体的可能转化方式, figureFileSmall=KcyH/sB5llom962JTzrgKw==, figureFileBig=QFx+DeIKRrJZuhdqHabyzA==, tableContent=null), ArticleFig(id=1195498846781489972, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195386782939394293, language=EN, label=Fig.12, caption=Structure transformation pathway of tacrolimus diene under positive ion mode, figureFileSmall=FVkqsbieb6QwjrMtndQD9w==, figureFileBig=OoapGbJDNny0phRT2jfcIg==, tableContent=null), ArticleFig(id=1195498846840210229, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195386782939394293, language=CN, label=图12, caption=他克莫司二烯可能的转化方式, figureFileSmall=FVkqsbieb6QwjrMtndQD9w==, figureFileBig=OoapGbJDNny0phRT2jfcIg==, tableContent=null), ArticleFig(id=1195498846898930486, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195386782939394293, language=EN, label=Fig.13, caption=Structure transformation pathway of tacrolimus lactone isomer under positive ion mode, figureFileSmall=954/A+Nv229KtOJD3IHjgQ==, figureFileBig=hTu5iX1i7x7g4uwqtGCWlw==, tableContent=null), 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journalId=1190317699101192196, articleId=1195386782939394293, language=EN, label=Fig.15, caption=Structure transformation pathway of tacrdimus 8-epimer under positive ion mode, figureFileSmall=In/1Ksq76X8BrMVi9MYriA==, figureFileBig=1AtEWTQDq9qCegdopIJD+Q==, tableContent=null), ArticleFig(id=1195498847217697595, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195386782939394293, language=CN, label=图15, caption=他克莫司8位差向异构体的可能转化方式, figureFileSmall=In/1Ksq76X8BrMVi9MYriA==, figureFileBig=1AtEWTQDq9qCegdopIJD+Q==, tableContent=null), ArticleFig(id=1195498847289000764, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195386782939394293, language=EN, label=Fig.16, caption=Structure transformation pathway of tacrolimus related compound Ⅵ and 8-epimer of related compound Ⅵ under positive ion mode, figureFileSmall=NK0fCx8MY6Cu+Q/6bqL5qw==, figureFileBig=WgfVxPRC2tIolWvjcU8M2A==, tableContent=null), ArticleFig(id=1195498847356109629, 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articleId=1195386782939394293, language=EN, label=Fig.18, caption=Structure transformation pathway of related compound Ⅷ under positive ion mode, figureFileSmall=HRcsMqpZhtOT9KUtpoowhQ==, figureFileBig=ZMKhBfTYL8k54fJGRhDTOQ==, tableContent=null), ArticleFig(id=1195498847603573569, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195386782939394293, language=CN, label=图18, caption=他克莫司关物质Ⅷ的可能转化方式, figureFileSmall=HRcsMqpZhtOT9KUtpoowhQ==, figureFileBig=ZMKhBfTYL8k54fJGRhDTOQ==, tableContent=null), ArticleFig(id=1195498848656343874, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195386782939394293, language=EN, label=Tab.1, caption=

Multi-atage mass fragment ions of tacrolimus and its impurities

, figureFileSmall=null, figureFileBig=null, tableContent=
Name tR m/z(QMI) δ Molecular formula m/z (MFI)
Tacrolimus 1.00 821.515 80 0.691 C44H69NO12 786.48,768.47,750.46,736.44,718.43,576.32,558.31,548.32,532.29,
266.10,254.10,234.11,130.09,84.08
Tacrolimus diene 8-epimer 0.62 803.505 24 -0.743 C44H67NO11 786.48,768.47,750.46,736.44,718.43,548.32,532.29,266.10,254.10,
234.11,130.09,84.08
Tacrolimus related compound Ⅷ 0.68 793.520 89 -2.807 C43H69NO11 758.48,740.47,722.46,708.44,690.44,548.32,530.31,520.32,504.30,
130.09,84.08
Tacrolimus diene 0.77 803.505 24 -0.395 C44H67NO11 786.48,768.47,750.46,736.44,718.43,548.32,532.29,266.10,254.10,
234.11,130.09,84.08
Tacrolimus lactone isomer 0.80 821.515 80 0.484 C44H69NO12 786.48,768.47,750.46,736.44,718.43,548.32,532.29,266.10,254.10,
234.11,130.09,84.08
Tacrolimus 8-epimer 0.82 821.515 80 -1.500 C44H69NO12 786.48,768.47,750.46,736.44,718.43,576.32,558.31,548.32,532.29,
266.10,254.10,234.11,130.09,84.08
Tacrolimus regioisomer 0.86 821.515 80 0.825 C44H69NO12 786.48,768.47,750.46,736.44,718.43,576.32,558.31,548.32,532.29,
266.10,254.10,234.11,130.09,84.08
Tacrolimus 19-epimer 1.11 821.515 80 0.643 C44H69NO12 786.48,768.47,750.46,736.44,718.43,576.32,558.31,548.32,532.29,
266.10,254.10,234.11,130.09,84.08
Tacrolimus open ring 1.27 821.515 80 -1.098 C44H69NO12 786.48,768.47,750.46,736.44,718.43,576.32,558.31,548.32,532.29,
266.10,254.10,234.11,130.09,84.08
Tacrolimus related compound Ⅵ 1.76 793.520 89 -2.744 C43H69NO11 619.42,601.41,583.40,569.38,551.37,409.26
Tacrolimus related compound 8-epimer 1.88 793.520 89 -2.731 C43H69NO11 619.42,601.41,583.40,569.38,551.37,409.26
), ArticleFig(id=1195498848731841347, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195386782939394293, language=CN, label=表1, caption=

他克莫司及各降解产物的多级碎片离子

, figureFileSmall=null, figureFileBig=null, tableContent=
Name tR m/z(QMI) δ Molecular formula m/z (MFI)
Tacrolimus 1.00 821.515 80 0.691 C44H69NO12 786.48,768.47,750.46,736.44,718.43,576.32,558.31,548.32,532.29,
266.10,254.10,234.11,130.09,84.08
Tacrolimus diene 8-epimer 0.62 803.505 24 -0.743 C44H67NO11 786.48,768.47,750.46,736.44,718.43,548.32,532.29,266.10,254.10,
234.11,130.09,84.08
Tacrolimus related compound Ⅷ 0.68 793.520 89 -2.807 C43H69NO11 758.48,740.47,722.46,708.44,690.44,548.32,530.31,520.32,504.30,
130.09,84.08
Tacrolimus diene 0.77 803.505 24 -0.395 C44H67NO11 786.48,768.47,750.46,736.44,718.43,548.32,532.29,266.10,254.10,
234.11,130.09,84.08
Tacrolimus lactone isomer 0.80 821.515 80 0.484 C44H69NO12 786.48,768.47,750.46,736.44,718.43,548.32,532.29,266.10,254.10,
234.11,130.09,84.08
Tacrolimus 8-epimer 0.82 821.515 80 -1.500 C44H69NO12 786.48,768.47,750.46,736.44,718.43,576.32,558.31,548.32,532.29,
266.10,254.10,234.11,130.09,84.08
Tacrolimus regioisomer 0.86 821.515 80 0.825 C44H69NO12 786.48,768.47,750.46,736.44,718.43,576.32,558.31,548.32,532.29,
266.10,254.10,234.11,130.09,84.08
Tacrolimus 19-epimer 1.11 821.515 80 0.643 C44H69NO12 786.48,768.47,750.46,736.44,718.43,576.32,558.31,548.32,532.29,
266.10,254.10,234.11,130.09,84.08
Tacrolimus open ring 1.27 821.515 80 -1.098 C44H69NO12 786.48,768.47,750.46,736.44,718.43,576.32,558.31,548.32,532.29,
266.10,254.10,234.11,130.09,84.08
Tacrolimus related compound Ⅵ 1.76 793.520 89 -2.744 C43H69NO11 619.42,601.41,583.40,569.38,551.37,409.26
Tacrolimus related compound 8-epimer 1.88 793.520 89 -2.731 C43H69NO11 619.42,601.41,583.40,569.38,551.37,409.26
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基于高效液相色谱-高分辨串联质谱的他克莫司软膏杂质谱研究
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布仁 1 , 周刚 2 , 盛华 1 , 莲花 1 , 曹慧敏 3 , 朱召贞 3 , 白文明 1, *
中国药学杂志 | 论著 2024,59(1): 78-87
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中国药学杂志 | 论著 2024, 59(1): 78-87
基于高效液相色谱-高分辨串联质谱的他克莫司软膏杂质谱研究
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布仁1, 周刚2, 盛华1, 莲花1, 曹慧敏3, 朱召贞3, 白文明1, *
作者信息
  • 1 内蒙古医科大学药学院, 呼和浩特 010110
  • 2 内蒙古自治区药品检验研究院, 呼和浩特 010020
  • 3 山东瑞安药业有限公司, 济南 250013

    • 布仁,男,本科,副教授 研究方向:药效物质基础与药物质量控制研究

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*白文明,男,博士,副教授 研究方向:药效物质基础与药物质量控制研究 Tel:(0471)6653144
Impurity Profile Study of Tacrolimus Ointment Based on High Performance Liquid Chromatography-High Resolution Mass Spectrometry
BU Ren1, ZHOU Gang2, SHENG Hua1, LIAN Hua1, CAO Huimin3, ZHU Zhaozhen3, BAI Wenming1, *
Affiliations
  • 1 College of Pharmacy, Inner Mongolia Medical University, Hohhot 010110, China
  • 2 Inner Mongolia Institutes for Drug Control, Hohhot 010020, China
  • 3 Shandong Ryan Pharmaceutical Co., Ltd., Jinan 250013, China
出版时间: 2024-01-08 doi: 10.11669/cpj.2024.01.010
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摘要
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目的 研究他克莫司软膏的杂质谱,为仿制药质量标准制定提供依据。方法 采用高效液相色谱-高分辨串联质谱联用技术分析强制破坏后的他克莫司软膏杂质,根据一级、二级质谱数据结合杂质的质谱裂解方式,推测各杂质的来源和分子结构。结果 他克莫司软膏强制破坏后,共产生10个杂质,其中包括3组同分异构体。 结论 本研究建立的杂质谱分析方法为他克莫司软膏的质量控制和工艺优化提供了参考依据。

他克莫司软膏  /  杂质谱  /  裂解方式  /  高效液相色谱-高分辨串联色谱

OBJECTIVE To investigate the impurity profile of tacrolimus ointment and lay a foundation for the establishment of generic drug quality standard. METHODS HPLC-HRMS/MS was adopted to analyze the impurities in destroyed tacrolimus ointment. According to the primary and secondary mass spectrometry data combined with the mass spectrometry fragmentation patterns of impurities, the source and molecular structures of the impurities were speculated. RESULTS Tacrolimus ointment totally produced 10 impurities after destructive test, wherein contained three groups of isomers. CONCLUSION The analysis method of impurity profile established in this study provides a reference basis for the quality control and process optimization of tacrolimus ointment.

tacrolimus ointment  /  impurity profile  /  fragmentation pattern  /  HPLC-HRMS/MS
布仁, 周刚, 盛华, 莲花, 曹慧敏, 朱召贞, 白文明. 基于高效液相色谱-高分辨串联质谱的他克莫司软膏杂质谱研究. 中国药学杂志, 2024 , 59 (1) : 78 -87 . DOI: 10.11669/cpj.2024.01.010
BU Ren, ZHOU Gang, SHENG Hua, LIAN Hua, CAO Huimin, ZHU Zhaozhen, BAI Wenming. Impurity Profile Study of Tacrolimus Ointment Based on High Performance Liquid Chromatography-High Resolution Mass Spectrometry[J]. Chinese Pharmaceutical Journal, 2024 , 59 (1) : 78 -87 . DOI: 10.11669/cpj.2024.01.010
正文
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他克莫司(tacrolimus)为大环内酯类化合物,是由筑波链霉菌(Streptomyces tsukubaensis)的发酵产物中分离得到的第二代免疫抑制剂,通过抑制钙调神经磷酸酶,抑制T细胞内钙依赖性信号传导通路,阻止淋巴因子的基因转录,从而发挥免疫抑制的作用[1]。多项临床试验证明,他克莫司的疗效是环孢素的10~100倍,且不会引起高血压、高血脂等环孢素副反应,同时还具有抗真菌、抗病毒、促神经再生等活性[2-3]。由于他克莫司在肝、肾、心等器官移植治疗中的显著疗效目前已在日本、美国等多个国家上市,是对抗自身免疫性疾病和器官移植治疗过程中出现的排异反应的一线治疗药物[4-6]。
仿制药生产是促进药品价格竞争、降低医药成本及防止市场垄断的有效手段[7]。药品中杂质的种类和含量总称为杂质谱,杂质谱研究能够为仿制药生产过程中的原料药稳定性评价和药品质量标准的制定提供依据。高效液相色谱-高分辨串联质谱法(HPLC-HRMS/MS)是快速筛查杂质并推定其结构的有效分析手段,相较于传统的液质联用技术而言,具有方法开发简单、分析速度快、质量范围宽、灵敏度高、可检测成分种类多数量大等优点。本研究采用HPLC-HRMS/MS法对待上市他克莫司软膏剂进行杂质谱分析,结合美国药典和日本药典确定杂质种类和裂解方式,建立他克莫司的杂质谱,为他克莫司仿制药一致性评价提供基础数据。
1 仪器与试药
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U-3000双三元液相色谱仪(美国 Thermofisher公司); Q-Exactive高分辨串联质谱仪(美国 Thermofisher公司);AUW220D电子天平(日本 Shimadzu公司);SYNS50001超纯水机(美国,Millipore公司);Xcalibur 3.1(美国 Thermofisher公司)。
他克莫司软膏(厂家A,待上市);他克莫司(4-EOD-191-1,97.00%,250 mg,TRC)、8位差向异构体(2062-003A5,94.80%,10 mg,TLC)、内酯异构体(2706-077A4,96.20%,10 mg,TLC)、他克莫司二烯(BLD-TKMSSX-170912,98.43%,25 mg)(山东博洛德生物科技有限公司);过氧化氢、盐酸、氢氧化钠均为分析纯;乙腈、正丁基氯、异丙醇、正己烷、醋酸铵均为质谱级试剂;水为自制超纯水(电阻率不低于18.2 MΩ.cm)(市售)。
2 方法
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2.1 HPLC-HRMS/MS测定
液相色谱条件:串联使用两根Supelcosil LC-FUJI-Diol色谱柱(4.6 mm×250 mm,5 μm);柱温:28 ℃;柱前流动相:正丁基氯-乙腈-正己烷(体积比20:10:70);流速:1.350 mL·min-1;柱后改性流动相:异丙醇-10 mmol·L-1醋酸铵异丙醇溶液(体积比70∶30);流速:0.3 mL·min-1;检测波长:225 nm;进样量:20 μL;运行时间:他克莫司峰保留时间的3倍。为结合美国药典推定杂质结构,本研究采用的色谱条件与美国药典一致。同时,为保证柱前流动相不分层,配制时应按照正丁基氯、乙腈、正己烷的顺序混合,且使用温度应保持在20 ℃附近。
质谱条件:采用ESI离子源正离子模式检测,离子源电压分别为4 kV(+),采用full ms-ddms2扫描方式(m/z 100~1 100 ),鞘气体积流速为40 L·min-1(+),碎裂电压300 V;干燥气温度350 ℃;饱和辅助气体积流速为2 L·min-1;喷雾气压45 psi;高纯N2为雾化气。
2.2 供试品溶液的制备
2.2.1 系统适用性试验溶液
取他克莫司对照品和他克莫司有关化合物A对照品适量,加稀释剂(体积比1∶1∶1的正己烷-正丁基氯-乙腈)溶解并稀释制成每1 mL中分别约含0.1 mg的溶液。
2.2.2 强制降解溶液的制备
取他克莫司原料药约20 mg,精密称定,置安瓿瓶中,按照下述步骤进行强制降解试验,考察他克莫司在强酸、强碱、氧化、高温、光照射等条件下产生的降解产物。
酸破坏供试品溶液:加0.1 mol·L-1盐酸溶液1 mL,于110 ℃加热2 h,取出,放冷至室温,加0.1 mol·L-1氨水溶液中和,氮吹至干,用少许流动相洗涤3次,合并洗涤液,置10 mL量瓶中,用流动相稀释至刻度,摇匀,即得。
碱破坏供试品溶液:因他克莫司对碱极敏感,氢氧化钠条件下降解剧烈,故改为三乙胺制备碱破坏供试品溶液。加三乙胺0.5 mL,于60 ℃恒温烘箱加热14 h,取出,放冷至室温,加1 mol·L-1盐酸溶液中和,氮吹至干,用少许流动相洗涤3次,合并洗涤液,置10 mL量瓶中,用流动相稀释至刻度,摇匀,即得。
氧化破坏供试品溶液:加入体积分数3%过氧化氢溶液1 mL,于80 ℃恒温烘箱加热5 h,取出,放冷至室温,氮吹至干,用少许流动相洗涤3次,合并洗涤液,置10 mL量瓶中,加流动相稀释至刻度,摇匀,即得。
高温破坏供试品溶液:于120 ℃加热14 h,取出,放冷至室温,用少许流动相洗涤3次,合并洗涤液,置10 mL量瓶中,加流动相稀释至刻度,摇匀,即得。
光照破坏供试品溶液:4 500 lx光照21 d,取出,用少许流动相洗涤3次,合并洗涤液,置10 mL量瓶中,加流动相稀释至刻度,摇匀,即得。
3 结果
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他克莫司经强制降解试验共产生10个杂质,其中包括3组同分异构体。下面将对强制降解试验产生的各个杂质的具体来源及质谱裂解方式进行推测。
3.1 系统适用性
取系统适用性试验溶液20 μL,注入液相色谱仪,记录色谱图,调节流速,使他克莫司主峰的保留时间约为15 min,他克莫司峰和他克莫司有关化合物A峰之间的分离度不小于1.5、拖尾因子不大于1.1,表明分离度及拖尾因子均符合要求,仪器的系统适用性良好。
3.2 他克莫司强制降解杂质的HPLC-HRMS/MS分析
取各破坏供试品溶液20 μL,注入液相色谱仪,记录色谱图(图1~5)。分析质谱一级全扫及对应数据依赖二级质谱图,共得到3组10个降解产物。各组精确质量数及计算分子式见表1。
3.3 他克莫司裂解方式解析
原料药准分子离子峰[M+NH4]+m/z 821.515 80的二级质谱图中,m/z 786.478 69、m/z 768.468 12、m/z 750.457 56为母离子的连续脱水峰,m/z 736.441 91为m/z 768.468 12脱甲醇峰,m/z 718.431 34为m/z 750.457 56脱甲醇峰。推测裂解方式见图6。
m/z 576.316 71、m/z 558.306 14、m/z 548.321 79、m/z 532.290 49为m/z 786.478 69 α-裂解开环系列产物,推测裂解方式见图7。
19位羟基脱水后生成的不饱和六元环可RDA开环裂解生成m/z 254.102 30,推测裂解方式见图8。图9~10为他克莫司其他主要碎片离子正离子模式下的可能裂解途径。以上推断碎片均与精确质量数计算结果相符(δ<5×10-6)。
3.4 各强制降解杂质的种类和来源
依据他克莫司的裂解方式及质谱数据并参考色谱行为,降解杂质结构及其裂解方式推测如下。
3.4.1 酸破坏降解杂质
相对保留时间0.62和0.77处有m/z 803.505 24的准分子离子峰[M+NH4]+,经精确质量数计算分子式应为C44H67NO11(δ<5×10-6),是他克莫司的脱水产物。两峰二级质谱图一致,与他克莫司二级质谱图对比m/z 576.316 71、m/z 558.306 14碎片峰消失,应为5位羟基受热脱水。其他碎片裂解方式与他克莫司相同。0.77处峰与他克莫司二烯对照品保留时间及二级质谱一致,与美国药典[8]记载相符,推断为他克莫司二烯。0.62处峰与他克莫司二烯二级质谱一致,保留时间靠前,应为他克莫司二烯的8位差向异构体,含量较高可能是由于二烯的生成有利于7位羰基形成烯醇式互变平衡,进而转变为8位差向异构,见图11。
他克莫司二烯还出现原料药的高温破坏样品中。在他克莫司二烯的二级质谱中与5位羟基相关的m/z 576.316 71、m/z 558.306 14碎片峰消失,故推断降解途径应为β-羟基酮受热脱水,见图12。
3.4.2 高温破坏降解杂质
相对保留时间0.80、0.86和1.11处有m/z 821.515 80的准分子离子峰[M+NH4]+,经精确质量数计算分子式应为C44H69NO12(δ<5×10-6),是他克莫司的同分异构体。0.80处峰与他克莫司二级质谱图对比m/z 576.316 71、m/z 558.306 14碎片峰消失,提示为5-位羟基发生变化,其他碎片裂解方式与他克莫司相同。其保留时间与内酯异构体对照品一致,与美国药典记载相符,推断为他克莫司内酯异构体。0.86和1.11处峰二级质谱与他克莫司一致,保留时间与美国药典记载的位置异构体和19位差向异构体相符,故推断0.86为他克莫司位置异构体,1.11为他克莫司19位差向异构体。
美国药典将19位差向异构体列为互变平衡化合物,不作为杂质。
内酯异构体,因高温破坏样品中未检出大环开环产物,故推断降解途径应为分子内酯交换反应,见图13。
位置异构体还出现在原料药的酸破坏样品中。因对应破坏样品中未检出大环开环产物,故推断降解途径应为克莱森重排,见图14。
3.4.3 碱破坏降解杂质
相对保留时间0.82和1.27处有m/z 821.515 80的准分子离子峰[M+NH4]+,经精确质量数计算分子式应为C44H69NO12(δ<5×10-6),是他克莫司的同分异构体。两峰二级质谱与他克莫司一致,保留时间与美国药典记载的8-位差向异构体和开环异构体相符,故推断0.82为他克莫司8位差向异构体,1.27为他克莫司开环异构体。美国药典将开环异构体列为互变平衡化合物,不作为杂质。
8位差向异构体降解途径为7位羰基的烯醇式互变异构,见图15。
3.4.4 光照破坏降解杂质
相对保留时间0.68、1.76和1.88处有m/z 793.520 89的准分子离子峰[M+NH4]+,经精确质量数计算分子式应为C43H69NO11(δ<5×10-6),是他克莫司脱羰产物。其中0.68处峰二级质谱与他克莫司相似,只是对应带碎片质荷比较他克莫司少m/z 28,其保留时间与日本药典记载有关物质Ⅷ相符,推断其为有关物质Ⅷ。1.76和1.88处峰二级质谱与他克莫司相差较大,其保留时间与日本药典记载有关物质Ⅵ相符,由于破坏时间较长(21 d),通过7位羰基形成8位差向互变平衡,故推断为有关物质Ⅵ及有关物质8位差向异构体,见图16。
有关物质Ⅵ裂解方式,见图17。
因对应破坏样品中未检出大环开环产物,所以推测有关物质Ⅷ为邻二酮脱羰,有关物质Ⅵ为邻二酮脱羰后开环,见图18。
4 讨论
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本实验以HPLC-HRMS/MS为主要研究手段,采用full ms-ddms2扫描模式筛查分析某厂家待上市(仿制药)他克莫司软膏的强制降解杂质。
在分析方法的开发过程中,本研究在参考了美国药典中有关物质分析的正相条件的基础上,经前期试验发现使用与正相系统互溶的醋酸铵异丙醇溶液作为柱后流动相时可显著改善离子化抑制效应,提高离子化效率,有效的保证了本研究所需灵敏度和检出限。另外,经文献调研和前期实验研究发现NaOH溶液碱破坏试验得到的降解杂质过多,与实际情况差异较大。所以,本研究采用了较弱的三乙胺作为碱破坏试验条件,降解得到了2个杂质,较接近于实际情况。结合一级、二级质谱数据和相关国家药典,通过推测他克莫司以及降解杂质的裂解途径,推定出10个降解杂质。他克莫司的降解产物主要分为两类。一类为脱水、脱羰不可逆降解,如他克莫司二烯、有关物质Ⅵ、Ⅷ等。另一类为平衡互变产物,如内酯、位置、8位差向、19位差向、开环异构体。而美国药典只将19位差向和开环异构体作为平衡互变产物不计入杂质,可能是因其较易形成互变平衡(室温4 h),而其他化合物需较长时间或较苛刻条件(高温、强酸)才能形成互变平衡。
本研究建立的基于HPLC-HRMS/MS的他克莫司软膏杂质谱分析方法简单且具有较强的规律性。
基金
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  • 内蒙古自治区自然科学基金面上项目资助(2020MS08045)
  • 内蒙古医科大学面上项目资助(YKD2021MS022)
  • 内蒙古医科大学他克莫司软膏补发试验资助(RH1900003513)
文献
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参考文献 引证文献
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JIN L Q, LU D, LIU Z, et al. Biosynthesis of immunosuppressant tacrolimus:a review[J]. Chin J Biotechnol(生物工程学报), 2023, 39(8):3095-3110. DOI: 10.13345/j.cjb.220994.
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WANG Z Z, ZHENG H, YANG B, et al. Correlation between intra-individual variability of tacrolimus and the prognosis of heart transplantation[J]. J Pract Med (实用医学杂志), 2022, 38(24):3145-3149.
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2024年第59卷第1期
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文章信息
doi: 10.11669/cpj.2024.01.010
  • 接收时间：2023-05-30
  • 首发时间：2025-11-12
  • 出版时间：2024-01-08
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出版历史
  • 收稿日期：2023-05-30
基金
内蒙古自治区自然科学基金面上项目资助(2020MS08045)
内蒙古医科大学面上项目资助(YKD2021MS022)
内蒙古医科大学他克莫司软膏补发试验资助(RH1900003513)
作者信息
    1 内蒙古医科大学药学院, 呼和浩特 010110
    2 内蒙古自治区药品检验研究院, 呼和浩特 010020
    3 山东瑞安药业有限公司, 济南 250013

通讯作者:

*白文明,男,博士,副教授 研究方向:药效物质基础与药物质量控制研究 Tel:(0471)6653144
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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
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