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Article(id=1210148013876572404, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1210148010437243088, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2022-0583, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1652284800000, receivedDateStr=2022-05-12, revisedDate=1654617600000, revisedDateStr=2022-06-08, acceptedDate=null, acceptedDateStr=null, onlineDate=1766451369971, onlineDateStr=2025-12-23, pubDate=1660233600000, pubDateStr=2022-08-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1766451369971, onlineIssueDateStr=2025-12-23, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1766451369971, creator=13701087609, updateTime=1766451369971, updator=13701087609, issue=Issue{id=1210148010437243088, tenantId=1146029695717560320, journalId=1189982191388893191, year='2022', volume='57', issue='8', pageStart='2245', pageEnd='2556', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1766451369151, creator=13701087609, updateTime=1766451533022, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1210148697808179705, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1210148010437243088, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1210148697808179706, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1210148010437243088, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=2461, endPage=2470, ext={EN=ArticleExt(id=1210148014304391434, articleId=1210148013876572404, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Analysis of metabolites of rocuronium bromide in human bile and the study of transmembrane transport mechanism, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

Rocuronium bromide is an acetylcholine N2 receptor antagonist, which can be used as an auxiliary drug for general anesthesia. It has been reported that rocuronium has two possible metabolic pathways: N-dealkylation and O-deacetylation, which are mainly taken up by liver and excreted by bile in the form of primary drugs. In this paper, the metabolites of rocuronium in human bile were detected by UHPLC-QE-orbitrap-MS, thirteen metabolites were detected, including eleven phase I metabolites and two phase II metabolites, eleven of which had not been previously reported. At the same time, HEK293 cells overexpressing transporter were used to explore the transmembrane transport mechanism of rocuronium, the results showed that rocuronium was the substrate of MATE1, OCT1, OATP1B1 and OATP1B3. The above research results enrich the metabolic pathway of rocuronium in vivo, and put forward the possible transport mechanism of liver uptake and bile excretion, which can better guide the accurate and safe clinical drug application. The collection of human bile samples in this study was approved by the ethics committee of Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (Approval Number: 2019-775-130-01).

, correspAuthors=Da-fang ZHONG, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2022 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=Ai-nan ZHOU, Zi-tao GUO, Jia-jun CHEN, Yun-quan LUO, Bo TAN, Xing-xing DIAO, Da-fang ZHONG), CN=ArticleExt(id=1210148016980357492, articleId=1210148013876572404, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=罗库溴铵在人胆汁中的代谢产物分析和转运机制研究, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

罗库溴铵是一种乙酰胆碱N2受体拮抗剂, 为全身麻醉辅助用药。已有文献报道罗库溴铵在体内存在N-去烷基化和去乙酰化两种可能代谢途径, 并主要以原形经肝脏摄取和胆汁排泄。本文采用UHPLC-QE-Orbitrap-MS法检测罗库溴铵在人胆汁中的代谢产物, 共检测到13种代谢产物, 包括I相代谢产物11种, II相代谢产物2种, 其中11种为首次报道的代谢产物, 罗库溴铵在人体内的主要代谢途径包括去乙酰化、内酰胺化、N-去烷基化、O-去烷基化、羟基化、乙酰化及葡萄糖醛酸化等。采用过表达转运体的HEK293细胞探索罗库溴铵的肝脏跨膜转运机制, 结果显示其为肝脏转运体MATE1、OCT1、OATP1B1和OATP1B3的底物。上述研究结果丰富了罗库溴铵体内代谢途径, 提出了肝脏摄取和胆汁排泄的可能转运机制, 可更好地指导临床精准安全用药。本研究中人体胆汁样本的采集是由上海中医药大学附属曙光医院伦理委员会批准(批件号: 2019-775-130-01)。

, correspAuthors=钟大放, authorNote=null, correspAuthorsNote=
*钟大放，Tel: 13482825842, E-mail:
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Br J Anaesth, 2000, 85: 717-723., articleTitle=Urinary, biliary and faecal excretion of rocuronium in humans, refAbstract=null), Reference(id=1210148026685977428, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210148013876572404, doi=10.1097/00000542-199911000-00022, pmid=null, pmcid=null, year=1999, volume=91, issue=null, pageStart=1305, pageEnd=1310, url=null, language=null, rfNumber=[14], rfOrder=13, authorNames=null, journalName=Anesthesiology, refType=null, unstructuredReference=Duvaldestin P, Slavov V, Rebufat Y, et al. Pharmacokinetics and pharmacodynamics of rapacuronium in patients with cirrhosis[J]. Anesthesiology, 1999, 91: 1305-1310., articleTitle=Pharmacokinetics and pharmacodynamics of rapacuronium in patients with cirrhosis, refAbstract=null), Reference(id=1210148026853749601, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210148013876572404, doi=null, pmid=null, pmcid=null, year=2015, volume=31, issue=null, pageStart=90, pageEnd=92, url=https://www.cnki.com.cn/Article/CJFDTOTAL-LCMZ202112003.htm, language=null, rfNumber=[15], rfOrder=14, authorNames=null, journalName=J Clin Anesthesiol (临床麻醉学杂志), refType=null, unstructuredReference=Mei Y, Yang M, Wang CY, et al. Association between OATP1B1 gene polymorphism and rocuronium induced muscle relaxation[J]. 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No.tR/minMetabolic pathwayFormulaMeasured
(m/z)		Error
(ppm)		LC-MS area (×107) aFragment ion (m/z)
Patient1Patient2
M012.34ParentC32H53N2O4529.400 30.57295.091 082.11487.353 1, 70.065 9, 112.112 6, 358.273 7, 413.316 2, 88.076 3, 340.264 0, 376.283 3, 427.332 7, 100.076 1
M112.84DeacetylationC30H51N2O3487.389 50.216.4432.51445.342 5, 70.065 8, 112.112 6, 358.273 5, 376.284 5, 88.076 3, 100.076 1
M212.38N-DealkylationC29H49N2O4489.366 6-4.290.210.31429.347 2, 471.358 7, 70.065 9, 88.076 3, 100.076 2
M316.73CarbonylationC30H49N2O4501.369 10.800.371.18459.321 5, 70.065 8, 112.112 6, 102.055 4
M411.61N-Dealkylation, O-DealkylationC30H51N2O4503.384 2-0.200.491.15461.337 1, 70.065 8, 112.112 6, 332.258 2, 387.299 9, 314.247 4, 350.369 0, 401.315 7, 100.075 7
M516.44CarbonylationC32H51N2O5543.379 30.1817.1546.94501.332 6, 70.065 9, 112.112 7, 102.055 4, 372.253 0, 427.295 5, 441.310 8
M6-111.08HydroxylationC32H53N2O5545.395 00.180.040.15110.097 0, 128.107 3, 358.274 5, 88.076 1, 340.263 7, 358.274 5
M6-211.76HydroxylationC32H53N2O5545.394 9-0.020.380.85503.347 8, 374.268 8, 70.065 8, 112.112 6, 429.315 5, 88.076 3, 104.071 0
M6-312.76HydroxylationC32H53N2O5545.395 3-0.730.103.7570.065 9, 112.112 6, 442.331 5, 400.284 4, 340.262 8, 358.273 9
M7-115.36Carbonylation, hydroxylationC32H51N2O6559.375 31.970.170.34Undetected
M7-215.76Carbonylation, hydroxylationC32H51N2O6559.374 50.540.761.28517.327 2, 70.065 9, 112.112 6, 443.288 6, 360.253 7, 118.050 0
M7-316.16Carbonylation, hydroxylationC32H51N2O6559.374 60.720.921.55517.327 3, 70.065 9, 112.112 6, 443.289 8, 360.253 2, 118.050 1
M813.94AcetylationC34H55N2O5571.410 70.350.601.43529.363 4, 469.343 3, 70.065 9, 112.112 6, 358.273 9, 340.263 4, 88.076 0
M911.89GlucuronidationC38H61N2O10705.431 8-0.432.178.75663.384 6, 529.401 0, 487.353 3, 70.065 9, 112.112 7, 358.273 9, 340.262 7
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Analysis and identification of metabolites in human bile of rocuronium bromide using UHPLC-QE-Orbitrap-MS. aExtracted ion flow diagram of each metabolite was integrated

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No.tR/minMetabolic pathwayFormulaMeasured
(m/z)		Error
(ppm)		LC-MS area (×107) aFragment ion (m/z)
Patient1Patient2
M012.34ParentC32H53N2O4529.400 30.57295.091 082.11487.353 1, 70.065 9, 112.112 6, 358.273 7, 413.316 2, 88.076 3, 340.264 0, 376.283 3, 427.332 7, 100.076 1
M112.84DeacetylationC30H51N2O3487.389 50.216.4432.51445.342 5, 70.065 8, 112.112 6, 358.273 5, 376.284 5, 88.076 3, 100.076 1
M212.38N-DealkylationC29H49N2O4489.366 6-4.290.210.31429.347 2, 471.358 7, 70.065 9, 88.076 3, 100.076 2
M316.73CarbonylationC30H49N2O4501.369 10.800.371.18459.321 5, 70.065 8, 112.112 6, 102.055 4
M411.61N-Dealkylation, O-DealkylationC30H51N2O4503.384 2-0.200.491.15461.337 1, 70.065 8, 112.112 6, 332.258 2, 387.299 9, 314.247 4, 350.369 0, 401.315 7, 100.075 7
M516.44CarbonylationC32H51N2O5543.379 30.1817.1546.94501.332 6, 70.065 9, 112.112 7, 102.055 4, 372.253 0, 427.295 5, 441.310 8
M6-111.08HydroxylationC32H53N2O5545.395 00.180.040.15110.097 0, 128.107 3, 358.274 5, 88.076 1, 340.263 7, 358.274 5
M6-211.76HydroxylationC32H53N2O5545.394 9-0.020.380.85503.347 8, 374.268 8, 70.065 8, 112.112 6, 429.315 5, 88.076 3, 104.071 0
M6-312.76HydroxylationC32H53N2O5545.395 3-0.730.103.7570.065 9, 112.112 6, 442.331 5, 400.284 4, 340.262 8, 358.273 9
M7-115.36Carbonylation, hydroxylationC32H51N2O6559.375 31.970.170.34Undetected
M7-215.76Carbonylation, hydroxylationC32H51N2O6559.374 50.540.761.28517.327 2, 70.065 9, 112.112 6, 443.288 6, 360.253 7, 118.050 0
M7-316.16Carbonylation, hydroxylationC32H51N2O6559.374 60.720.921.55517.327 3, 70.065 9, 112.112 6, 443.289 8, 360.253 2, 118.050 1
M813.94AcetylationC34H55N2O5571.410 70.350.601.43529.363 4, 469.343 3, 70.065 9, 112.112 6, 358.273 9, 340.263 4, 88.076 0
M911.89GlucuronidationC38H61N2O10705.431 8-0.432.178.75663.384 6, 529.401 0, 487.353 3, 70.065 9, 112.112 7, 358.273 9, 340.262 7
), ArticleFig(id=1210148023712215769, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210148013876572404, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
TransporterURRRA
MATE111.3017.77%
OATP1B15.4411.25%
OATP1B32.1428.93%
OCT12.9266.48%
), ArticleFig(id=1210148023817073376, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210148013876572404, language=CN, label=Table 2, caption=

The uptake rate ratio (URR) and residual activity (RA) of transporter substrate screening test

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TransporterURRRA
MATE111.3017.77%
OATP1B15.4411.25%
OATP1B32.1428.93%
OCT12.9266.48%
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罗库溴铵在人胆汁中的代谢产物分析和转运机制研究
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周爱南 1 , 郭子涛 1 , 陈佳骏 2 , 罗运权 2 , 谭波 2 , 刁星星 1 , 钟大放 1, *
药学学报 | 研究论文 2022,57(8): 2461-2470
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药学学报 | 研究论文 2022, 57(8): 2461-2470
罗库溴铵在人胆汁中的代谢产物分析和转运机制研究
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周爱南1, 郭子涛1, 陈佳骏2, 罗运权2, 谭波2, 刁星星1, 钟大放1, *
作者信息
  • 1.中国科学院上海药物研究所, 上海 201203
  • 2.上海中医药大学附属曙光医院, 上海 201203

通讯作者:

*钟大放，Tel: 13482825842, E-mail:
Analysis of metabolites of rocuronium bromide in human bile and the study of transmembrane transport mechanism
Ai-nan ZHOU1, Zi-tao GUO1, Jia-jun CHEN2, Yun-quan LUO2, Bo TAN2, Xing-xing DIAO1, Da-fang ZHONG1, *
Affiliations
  • 1. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
  • 2. Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
出版时间: 2022-08-12 doi: 10.16438/j.0513-4870.2022-0583
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摘要
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罗库溴铵是一种乙酰胆碱N2受体拮抗剂, 为全身麻醉辅助用药。已有文献报道罗库溴铵在体内存在N-去烷基化和去乙酰化两种可能代谢途径, 并主要以原形经肝脏摄取和胆汁排泄。本文采用UHPLC-QE-Orbitrap-MS法检测罗库溴铵在人胆汁中的代谢产物, 共检测到13种代谢产物, 包括I相代谢产物11种, II相代谢产物2种, 其中11种为首次报道的代谢产物, 罗库溴铵在人体内的主要代谢途径包括去乙酰化、内酰胺化、N-去烷基化、O-去烷基化、羟基化、乙酰化及葡萄糖醛酸化等。采用过表达转运体的HEK293细胞探索罗库溴铵的肝脏跨膜转运机制, 结果显示其为肝脏转运体MATE1、OCT1、OATP1B1和OATP1B3的底物。上述研究结果丰富了罗库溴铵体内代谢途径, 提出了肝脏摄取和胆汁排泄的可能转运机制, 可更好地指导临床精准安全用药。本研究中人体胆汁样本的采集是由上海中医药大学附属曙光医院伦理委员会批准(批件号: 2019-775-130-01)。

代谢产物  /  罗库溴铵  /  人胆汁  /  UHPLC-QE-orbitrap-MS  /  转运体

Rocuronium bromide is an acetylcholine N2 receptor antagonist, which can be used as an auxiliary drug for general anesthesia. It has been reported that rocuronium has two possible metabolic pathways: N-dealkylation and O-deacetylation, which are mainly taken up by liver and excreted by bile in the form of primary drugs. In this paper, the metabolites of rocuronium in human bile were detected by UHPLC-QE-orbitrap-MS, thirteen metabolites were detected, including eleven phase I metabolites and two phase II metabolites, eleven of which had not been previously reported. At the same time, HEK293 cells overexpressing transporter were used to explore the transmembrane transport mechanism of rocuronium, the results showed that rocuronium was the substrate of MATE1, OCT1, OATP1B1 and OATP1B3. The above research results enrich the metabolic pathway of rocuronium in vivo, and put forward the possible transport mechanism of liver uptake and bile excretion, which can better guide the accurate and safe clinical drug application. The collection of human bile samples in this study was approved by the ethics committee of Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (Approval Number: 2019-775-130-01).

metabolite  /  rocuronium bromide  /  human bile  /  UHPLC-QE-Orbitrap-MS  /  transporter
周爱南, 郭子涛, 陈佳骏, 罗运权, 谭波, 刁星星, 钟大放. 罗库溴铵在人胆汁中的代谢产物分析和转运机制研究. 药学学报, 2022 , 57 (8) : 2461 -2470 . DOI: 10.16438/j.0513-4870.2022-0583
Ai-nan ZHOU, Zi-tao GUO, Jia-jun CHEN, Yun-quan LUO, Bo TAN, Xing-xing DIAO, Da-fang ZHONG. Analysis of metabolites of rocuronium bromide in human bile and the study of transmembrane transport mechanism[J]. Acta Pharmaceutica Sinica, 2022 , 57 (8) : 2461 -2470 . DOI: 10.16438/j.0513-4870.2022-0583
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罗库溴铵(化学结构式见图 1A) 是一种乙酰胆碱N2受体拮抗剂, 可竞争性占据神经肌肉接头突触后膜上的胆碱受体, 阻断乙酰胆碱的去极化作用而产生骨骼肌松弛作用, 临床上主要用于全身麻醉辅助用药, 具有起效迅速、不良反应低等特点, 是目前起效最快的非去极化肌肉松弛药[1-7]。
和其他肌肉松弛药一样, 罗库溴铵的给药剂量应个体化。近年来, 国内外对罗库溴铵的研究主要集中在不同人群中的药动学方面[8-10], 但对代谢途径, 特别是人体中的代谢产物研究较少。仅有个别文献涉及到了罗库溴铵的代谢产物(图 1B和C) 研究, 分别为Kleef等[11]建立了柱前衍生的液相色谱-荧光法, 检测体液与组织匀浆中罗库溴铵及其可能代谢产物(去乙酰化和N-去烷基化代谢产物); Ling等[12]建立了GC-MS法检测人体血浆中的罗库溴铵和去乙酰化代谢产物, 由于方法检测灵敏度较低, 人体血浆中并未检测出可能的去乙酰化代谢产物; Proost等[13]研究了罗库溴铵及其潜在代谢产物在38名麻醉手术患者的排泄情况, 研究结果显示在人体不同的生物基质中, 均能检测出微量的去乙酰化代谢产物, N-去烷基化代谢产物仅在胆汁中有微量检出, 证明人体内存在这两种代谢产物。
罗库溴铵由静脉注射给药, 主要通过肝脏代谢, 据报道血浆清除由肝脏摄取和胆道排泄为主, 少量经尿液排出[13, 14]。肝脏摄取和胆汁排泄能够显著影响药物的系统暴露量, 从而影响药理作用和毒性等, 因此有必要了解罗库溴铵的转运机制, 以更好地指导临床用药。目前有文献报道罗库溴铵的跨膜转运和转运体有关, 梅杨等[15]研究发现人体肝脏转运体有机阴离子转运多肽1B1 (organic anion transporting polypeptide 1B1, OATP1B1) 的基因多态性是导致罗库溴铵药效个体差异的原因之一, 间接说明OATP1B1可能是其肝脏摄取转运体; Montfoort等[16]报道罗库溴铵由于分子量较大, 且正电荷集中在体积较大的环状结构中的季铵盐阳离子, 其在肝脏中的转运主要由有机阴离子转运多肽(organic anion transporting polypeptide, OATP) 介导, 而分子量较小亲水性的季铵盐阳离子化合物如胆碱等在肝脏中的摄取主要由有机阳离子转运体(organic cation transporter, OCT) 介导。但对罗库溴铵基于转运体的肝脏清除研究未有报道。
本论文目的是研究罗库溴铵在人胆汁中的可能代谢产物, 以完善罗库溴铵人体代谢途径。同时探索罗库溴铵的肝脏跨膜转运机制, 为临床个体化用药和药物相互作用提供指导。
材料与方法
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药品与试剂  罗库溴铵注射液(5 mL: 50 mg, 默沙东制药有限公司); 罗库溴铵对照品(纯度98%) 和内标维拉帕米(纯度98%), 大连美仑生物技术有限公司; 甲醇(色谱纯)、乙腈(色谱纯) 和二甲基亚砜(色谱纯), 德国Merck公司; 醋酸铵(色谱纯, 美国ROE公司); 甲酸(色谱纯, 德国Fluka公司)。去离子水由法国Millipore纯水仪制得。Hank's平衡盐溶液(Hanks' balanced salt solution, HBSS)、BCA蛋白浓度测定试剂盒(MA0082-3-Oct-22E) 购于大连美仑生物技术有限公司; 胎牛血清、达尔伯克氏改良伊格尔液(Dulbecco's modified Eagle's medium, DMEM) 购于美国Corning Cellgro公司; 青霉素-链霉素双抗溶液购于美国Gibco公司; D-多聚赖氨酸(poly-D-lysine, PDL) 购于美国BD公司。
细胞  转运体高表达细胞株HEK293-MATE1 (multidrug and toxin extrusion protein 1, MATE1)、HEK293-OATP1B1 (organic anion transporting polypeptide 1B1, OATP1B1)、HEK293-OATP1B3 (organic anion transporting polypeptide 1B3, OATP1B3)、HEK293-OCT1 (organic cation transporter 1, OCT 1) 和空白转染细胞均由上海药物代谢研究中心提供。
代谢产物鉴定
仪器  UHPLC-Q Exactive Plus Orbitrap高分辨质谱仪, 配有电喷雾电离源(ESI源), 美国ThermoFisher公司; Vanquish UHPLC液相色谱系统, 包括二元输液泵、自动进样器、柱温箱和脱气机, 美国ThermoFisher公司。采用ThermoFisher公司的Xcalibur 4.2软件进行数据采集, 采用Xcalibur 4.2和Compound Discoverer 3.2.0软件进行数据分析。
色谱条件  色谱柱为Acquity UPLC HSS T3柱(100 mm × 2.1 mm ID, 1.8 μm粒径), 美国Waters公司; 柱温为40 ℃; 样品室温度为10 ℃; 流速为0.3 mL·min-1; 流动相: A相为含0.1%甲酸水溶液, B相为含0.1%甲酸的甲醇; 梯度洗脱: 0~3.0 min, 2% B; 3.0~17.0 min, 2%~60% B; 17.0~20.0 min, 60%~95% B; 21.5~25.0 min, 2% B。进样体积5.0 μL。
质谱条件  离子源为电喷雾离子源(HESI), 正离子扫描方式检测, 喷雾电压为3.5 kV, 毛细管温度为350 ℃, 辅助气温度为350 ℃, 鞘气流速为50 arb, 辅助气流速为50 arb, 检测方式为Full MS/dd-MS2, Full MS分辨率为70 000, dd-MS2分辨率为17 500, 碰撞气为高纯氮气, 碰撞能量(NCE) 为15、40、50 eV, TopN为6, 扫描范围为m/z 200~1 000。
胆汁样品采集  对两名胆囊切除患者进行胆囊切除手术, 收集给药(静脉注射0.6 mg·kg-1) 后约0.5 h内的胆汁样品, 于-20 ℃保存待测。手术前患者自愿签署书面知情同意书。
胆汁样品预处理  取100 μL胆汁样品, 加900 μL乙腈, 涡旋混合1 min, 4 ºC下14 000 r·min-1离心5 min。取900 μL上清, 氮气流吹干, 加150 μL的复溶剂(乙腈∶水=15∶85) 溶解, 涡旋混合2 min, 4 ℃下14 000 r·min-1离心5 min, 取上清进样分析。
转运体实验
仪器  Agilent 1290液相色谱串联6495三重四级杆质谱仪, 配有电喷雾电离源(ESI源) 和1290 Infinity液相色谱系统, 包括二元输液泵、自动进样器、柱温箱和脱气机, 美国Agilent公司。采用Agilent公司的Masshunter软件进行数据采集和分析。
色谱条件  色谱柱为Agilent Eclipse Plus C18柱(50 mm × 3 mm ID, 1.8 μm粒径), 美国Agilent公司; 柱温为40 ℃; 样品室温度为10 ℃; 流速为0.4 mL·min-1; 流动相: A相为含0.005 mol·L-1醋酸铵水溶液, B相为含0.1%甲酸的乙腈; 梯度洗脱: 0~0.5 min, 5%~50% B; 0.5~0.8 min, 50%~90% B; 0.8~2.0 min, 90%~95% B; 3.01~3.5 min, 5% B。进样体积4.0 μL。
质谱条件  离子源为电喷雾离子源(ESI), 正离子扫描方式检测, 毛细管电压为4 000 V, 锥孔电压为380 V, 干燥气温度为250 ℃, 干燥气流量为14 L·min-1, 雾化气压力为50 psi, 鞘气温度为325 ℃, 鞘气流量为11 L·min-1。采用多反应监测(MRM) 方法定量, 罗库溴铵和内标维拉帕米的定量离子对分别为529.4→487.6和455.4→165.3, 碰撞能量均为40 V。
细胞培养  以DEME为培养基(含10% FBS、1% GlutaMAX-I、100 u·mL-1青霉素、100 μg·mL-1链霉素和1%非必需氨基酸), 在含5% CO2湿润的37 ℃培养箱中培养转运体细胞。待细胞生长达到80%~90%融合时, 以0.05%的胰酶消化细胞; 消化后的细胞以5×104/孔的密度接种至PDL包被的96孔板中, 置于5% CO2湿润的37 ℃培养箱中培养48 h, 进行转运体细胞摄取实验。
底物筛查实验  摄取开始之前弃去原有细胞培养液, 用37 ℃预热的HBSS溶液清洗细胞3次后, 向每孔中加入100 μL 37 ℃预热的HBSS溶液平衡10 min。吸去孔中HBSS溶液, 向每孔分别加入100 μL含或不含阳性抑制剂的待测化合物(浓度为10 μmol·L-1) 的HBSS溶液, 摄取时间为10 min, 实验设置三样本。摄取过程结束后, 快速移去孔中HBSS溶液, 以终止摄取反应; 随后用冰冷的HBSS溶液(不含药物) 清洗细胞3次, 去除细胞表面的药物。每孔加入50 μL的1 mol·L-1氢氧化钠溶液, 细胞板在室温下孵育10 min, 然后每孔加入1 mol·L-1盐酸溶液50 μL。从每孔取70 μL样品与70 μL乙腈混合, LC-MS/MS检测细胞内化合物的摄取情况。以BCA法测定的蛋白浓度加以校正。
细胞样品预处理  将100 μL细胞样品与100 μL内标(含有20.0 ng·mL-1的维拉帕米, 以乙腈配制) 混合加入至96孔(1.5 mL) 深孔板中, 涡旋15 min, 在4 ℃下3 700 r·min-1离心15 min后, 取出180 μL上清, 4 μL进样分析。
计算公式  通过计算化合物在摄取转运体细胞株中的摄取速率(uptake rate, UR) 与在空白转染细胞中的比值(uptake rate ratio, URR) 是否大于2来评价是否是摄取转运体的底物。通过计算各个转运体在抑制剂存在时底物的摄取速率变化, 即剩余活性(residual activity, RA) 来评价是否是摄取转运体底物。摄取速率的单位是pmol·min-1·mg-1, 计算公式如下:
$ \mathrm{摄}\mathrm{取}\mathrm{速}\mathrm{率}\left(\mathrm{U}\mathrm{R}\right)=\frac{{C}_{\mathrm{细}\mathrm{胞}\mathrm{裂}\mathrm{解}\mathrm{液}}\times \mathrm{ }1000}{{t}_{\mathrm{作}\mathrm{用}\mathrm{时}\mathrm{间}}\times {M}_{\mathrm{蛋}\mathrm{白}\mathrm{量}}} $
$ \mathrm{摄}\mathrm{取}\mathrm{速}\mathrm{率}\mathrm{比}\mathrm{值}\left(\mathrm{U}\mathrm{R}\mathrm{R}\right)=\frac{\mathrm{U}{\mathrm{R}}_{\mathrm{T}}}{\mathrm{U}{\mathrm{R}}_{\mathrm{V}}} $
式1和2中, C细胞裂解液指样品中的药物浓度(nmol·L-1), t作用时间为孵育时间(min), M蛋白量指细胞裂解液的蛋白浓度(μg·mL-1)。URT指在过表达转运体的HEK293细胞中的摄取速率, URV指在作为空白对照的HEK293细胞中的摄取速率。
$ \mathrm{剩}\mathrm{余}\mathrm{活}\mathrm{性}\left(\mathrm{R}\mathrm{A}\right)=\frac{\mathrm{U}{\mathrm{R}}_{\mathrm{C}\mathrm{O}}}{\mathrm{U}{\mathrm{R}}_{\mathrm{A}\mathrm{l}\mathrm{o}\mathrm{n}\mathrm{e}}}\times \mathrm{ }100\% $
式3中, URCO指有抑制剂存在时, 化合物在过表达转运体的HEK293细胞中的摄取速率, URAlone指化合物单独在过表达转运体的HEK293细胞中的摄取速率。
结果
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1 罗库溴铵在人胆汁中的代谢产物分析
1.1 罗库溴铵对照品色谱和质谱分析
良好的分离分析条件可使待测药物、代谢产物同生物样本中的内源性物质具有不同的保留时间和良好的峰形, 这样不仅可避免代谢物质谱解析复杂化, 同时可降低同一时间多离子出峰带来的离子抑制的影响。本实验主要通过流动相的组成、梯度洗脱等条件的优化, 最终得到罗库溴铵对照品的保留时间为12.34 min。取罗库溴铵对照品溶液(1 μg·mL-1) 进行质谱分析。主要生成正离子盐根[M]+离子(m/z 529.400 1) (图 2A)。高碰撞能量质谱图中(图 2A), 主要碎片离子为m/z 487.353 1、70.065 9、112.112 6、358.274 0、413.316 4、376.284 6、340.263 7、88.076 3、427.333 7等。根据罗库溴铵的结构特点和碎片离子, 推测其可能的质谱裂解规律(图 2B)。由于代谢产物是由原形药物在体内经酶催化产生的生物转化物, 与原形药物具有相似的母核结构, 因此可根据原形药物的特征碎片离子和质谱裂解规律来推测代谢产物的可能结构。
1.2 代谢产物分析
采用ThermoFisher公司的Xcalibur 4.2和Compound Discoverer 3.2.0软件对人胆汁中的UHPLC-QE-Orbitrap-MS数据进行分析, 以原形药物为研究基础, 通过与已知对照品比对保留时间、准确分子质量、碎片离子来确定原形药物。利用高分辨质谱数据分子离子峰、误差值、保留时间进行初步判断; 由于代谢产物与原形药物具有相似的母核结构, 因而具有相似的质谱裂解规律, 应用Compound Discoverer 3.2.0软件建立代谢产物鉴定模板, 结合质量亏损、特征离子等进行代谢产物的进一步表征。最终从人胆汁样品中分析鉴定出1个原形成分和13个可能的代谢产物(表 1), 胆汁样品的总离子流色谱图见图 3。
1.2.1 M1的表征
M1的保留时间为12.84 min, 准分子离子峰为487.389 5 ([M]+, C30H51N2O3), 比原形少了C2H2O, 丢失42 Da。在高碰撞能量下, 生成m/z 445.342 5、70.065 8、112.112 6、358.273 5、376.284 5等碎片离子, 其中m/z 70.065 8、112.112 6、358.273 5、376.284 5碎片离子与原形相同, m/z 445.342 5碎片离子比M0的特征碎片离子m/z 487.353 1少42 Da。推测M1为文献[11-13]报道的去乙酰化代谢产物(图 4)。
由于M1可能是酯水解产物, 其可不经代谢, 在样品的处理过程中也有可能产生。为证明样品的处理过程不会产生该物质, 采用将罗库溴铵对照品加入空白胆汁样品中, 后按“胆汁样品预处理”方法处理样品, 进样分析, 结果该样品中未检出M1, 因此可说明胆汁样品中检出的M1是经肝脏代谢产生。
1.2.2 M2的表征
M2的保留时间为12.38 min, 准分子离子峰为489.366 6 ([M]+, C29H49N2O4), 比原形少了C3H4, 丢失40 Da。在高碰撞能量下, 生成m/z 429.347 2、471.358 7、70.065 9、88.076 3等碎片离子, 其中m/z 70.065 9和88.076 3碎片离子与原形相同, 碎片离子m/z 471.358 7由母离子丢失一分子H2O (18 Da), 随后碎片离子m/z 471.357 8丢失一分子C2H2O (42 Da), 得到碎片离子m/z 429.347 6。推测M2为文献[11-13]报道的N-去烷基(去烯丙基) 代谢产物(图 4)。
1.2.3 M3的表征
M3的保留时间为16.73 min, 准分子离子峰为501.369 1 ([M]+, C30H49N2O4), 比原形少了C2H4, 丢失28 Da。在高碰撞能量下, 生成m/z 459.321 5、70.065 8、112.112 6、102.055 4等碎片离子, 其中m/z 70.065 8、112.112 6碎片离子与原形相同, m/z 459.321 5碎片离子比M1的特征碎片离子m/z 445.342 5多14 Da, m/z 102.055 4比M0的特征碎片离子m/z 88.076 3 (吗啉环正离子) 多14 Da, 推测M3为去乙酰化, 并在吗啉环上形成内酰胺的代谢产物(图 4)。
1.2.4 M4的表征
M4的保留时间为11.61 min, 准分子离子峰为503.384 2 ([M]+, C30H51N2O4), 比原形少了C2H2, 丢失26 Da。在高碰撞能量下, 生成m/z 461.337 1、70.065 8、112.112 6、332.258 2、387.299 9、314.247 4、350.369 0、401.315 7等碎片离子, 其中m/z 70.065 8、112.112 6碎片离子与原形相同, m/z 461.337 1、332.258 2、387.299 9、314.247 4、350.369 0、401.315 7碎片离子分别比M0的特征碎片离子m/z 487.353 1、358.273 7、413.316 2、340.264 0、376.283 3、427.332 7少26 Da。推测M4为吗啉环N端和O端同时去烷基(C2H2) 代谢产物(图 4)。
1.2.5 M5的表征
M5的保留时间为16.44 min, 准分子离子峰为543.379 3 ([M]+, C32H51N2O5), 比原形少2个H, 多1个O, 增加14 Da。在高碰撞能量下, 生成m/z 501.332 6、70.065 9、112.112 7、102.055 4、372.253 0、427.295 5、441.310 8等碎片离子, 其中m/z 70.065 9、112.112 7碎片离子与原形相同, m/z 501.332 6、102.055 4、372.253 0、427.295 5、441.310 8碎片离子分别比M0的特征碎片离子m/z 487.353 1、88.076 3、358.273 7、413.316 2、427.332 7多14 Da。推测M5为吗啉环上产生的内酰胺代谢产物(图 5)。
1.2.6 M6的表征
在m/z 545.394 9 ([M]+, C32H53N2O5) 的提取离子流色谱图中, 可检测到3个色谱峰, 保留时间为11.08、11.76和12.76 min, 分别命名为M6-1、M6-2和M6-3。根据准确分子量和元素组成分析, 比原形多一个O (16 Da), 推测其为羟基化代谢产物; 结合各物质的特征碎片离子和质谱裂解规律, 推测各物质可能的氧化位点。M6-1的保留时间为11.08 min, 在高碰撞能量下, 生成m/z 128.107 3、358.274 5、88.076 1、340.263 7等碎片离子, 其中m/z 358.274 5、88.076 1、340.263 7碎片离子与原形相同, 碎片离子m/z 128.107 3比原形特征碎片离子m/z 112.112 6多一个O (16 Da), 推测M6-1羟基化位点在四氢吡咯环上。M6-2的保留时间为11.76 min, 在高碰撞能量下, 生成m/z 503.347 8、374.268 8、70.065 8、112.112 6、88.076 3、104.071 0等碎片离子, 其中m/z 70.065 8、112.112 6、88.076 3碎片离子与原形相同, 碎片离子m/z 503.347 8比原形特征碎片离子m/z 487.353 1多一个O (16 Da), 碎片离子m/z104.071 0比m/z 88.076 3 (吗啉环离子) 多一个O (16 Da), 推测M6-2氧化位点在吗啉环上。M6-3的保留时间为12.76 min, 在高碰撞能量下, 生成70.065 8和112.1126 6等碎片离子, 与原形相同, 推测M6-3氧化位点不在四氢吡咯环上, 在其左侧基团上。
1.2.7 M7的表征
在m/z 559.374 2 ([M]+, C32H51N2O6) 的提取离子流色谱图中, 可检测到3个色谱峰, 保留时间为15.36、15.76和16.16 min, 分别命名为M7-1、M7-2和M7-3。根据准确分子量和元素组成分析, 比原形多2个O (16 Da), 少2个H (2 Da), 增加30 Da, 推测其为羟基化和内酰胺化代谢产物; 结合各物质的特征碎片离子和质谱裂解规律, 推测各物质可能的代谢位点。M7-1的保留时间为15.36 min, 未检出碎片离子峰。M7-2与M7-3的保留时间分别为15.76、16.16 min, 在高碰撞能量下, 均生成一致的m/z 517.327 2、70.065 9、112.112 6、443.288 6、360.253 7、118.050 0等碎片离子, 其中m/z 70.065 9、112.112 6碎片离子与原形相同, 碎片离子m/z 517.327 2、443.288 6、118.050 0比原形特征碎片离子m/z 487.353 1、413.316 2、88.076 3多30 Da, m/z 118.050 0比吗啉环多2个O, 少2个H, 推测M7-2与M7-3羟基化和内酰胺化代谢位点均在吗啉环上。
1.2.8 M8的表征
M8的保留时间为13.94 min, 准分子离子峰为571.410 7 ([M]+, C34H55N2O5), 比原形多了C2H2O (42 Da)。在高碰撞能量下, 生成m/z 529.363 4、469.343 3、70.065 9、112.112 6、358.273 9、340.263 4、88.076 0等碎片离子, 其中m/z 70.065 9、112.112 6、358.273 9、340.263 4、88.076 0碎片离子与原形相同, 碎片离子m/z 529.363 4由母离子丢失一分子C2H2O (42 Da), 比M0的特征碎片离子m/z 487.353 1多42 Da, 随后碎片离子m/z 529.363 4丢失一分子H2O (18 Da)、丢失一分子烯丙基C3H4 (40 Da) 和2个H (2 Da), 得到碎片离子m/z 469.343 3。推测M8为乙酰化代谢产物, 乙酰化位点在羟基上(图 5)。
1.2.9 M9的表征
M9的保留时间为11.89 min, 准分子离子峰为705.431 8 ([M]+, C38H61N2O10), 比原形多了C6H8O6 (176 Da)。在高碰撞能量下, 生成m/z 663.384 6、529.401 0、487.353 3、70.065 9、112.112 7、358.273 9、340.262 7等碎片离子, 其中m/z 487.353 3、70.065 9、112.112 7、358.273 9、340.262 7碎片离子与原形相同, 碎片离子m/z 663.384 6由母离子丢失一分子烯丙基C3H4 (40 Da) 和2个H (2 Da), 比原形的特征碎片离子487.353 1多176 Da, 碎片离子m/z 529.401 0由母离子丢失一分子葡萄糖醛酸(glucuronide, Glu, 176 Da)。推测M9为一分子葡萄糖醛酸结合物代谢产物, 结合位点在羟基上(图 5)。
综合分析质谱数据, 推测罗库溴铵在人体中的主要代谢途径(图 6) 包括去乙酰化、N-去烷基化、O-去烷基化、内酰胺化、羟基化、乙酰化及葡萄糖醛酸化。其中, 内酰胺化代谢产物M5、内酰胺化和去乙酰化代谢产物M3、N-去烷基化和O-去烷基化代谢产物M4、乙酰化代谢产物M8、羟基化代谢产物M6-1/M6-2/M6-3、葡萄糖醛酸结合代谢产物M9、内酰胺化和羟基化代谢产物M7-1/M7-2/M7-3均为人体内新发现的罗库溴铵代谢产物。
2 不同转运体细胞对罗库溴铵的摄取
不同转运体细胞对罗库溴铵的摄取结果见图 7和表 2。在浓度为10 μmol·L-1, 摄取时间为10 min条件下, MATE1、OATP1B1、OATP1B3和OCT1中的摄取量分别是Mock的11.30、4.95、2.14和2.74倍。摄取倍数大于2时认为有主动摄取发生, 表明罗库溴铵是MATE1、OATP1B1、OATP1B3和OCT1转运体的底物。
讨论
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本研究采用UHPLC-QE-Orbitrap-MS高分辨质谱仪, 以质谱友好的0.1%甲酸水溶液-0.1%甲酸甲醇溶液为流动相体系, 采用亲水性ACQUITY UPLC HSS T3柱, 进行代谢产物的分离可获得较好原形药物和代谢产物的色谱保留和峰形。结合代谢产物鉴定软件, 表征了罗库溴铵在人胆汁中的代谢产物。2名胆囊切除手术患者静注罗库溴铵约0.5 h后, 在其胆汁中共检测到13种代谢物, 包括11种I相代谢物及2种II相代谢物, 其中11种代谢产物为首次报道。由于人胆汁样品不易获得, 通常使用受试者粪样替代, 用以研究药物的代谢, 但是由于有些代谢产物(如葡糖糖醛酸结合物) 在肠道菌群的作用下易发生降解而无法检出, 因此, 本论文采用人胆汁为研究对象, 可以获得更准确和全面的罗库溴铵在人体中的代谢途径。
从代谢物种类和质谱的相对峰面积比例来判断, 2名患者代谢产物种类和代谢途径一致, 定量也无明显差异。质谱峰面积结果显示, 内酰胺代谢产物M5、去乙酰化代谢产物M1和葡萄糖醛酸化代谢产物M9是含量相对较高的主要代谢产物, 但由于无代谢产物对照品, 且不同物质的质谱离子化程度差异, 无法准确判断真实含量的多少。
后续可尝试制备主要代谢产物M5的对照品, 经结构确证后, 进行定量及其他药代动力学研究。M5为在吗啉环上形成的内酰胺代谢产物, 在人体中相对含量较高, 是主要代谢产物; 此外还有去乙酰化和内酰胺化代谢产物M3, 羟基化和内酰胺代谢产物M7-1/M7-2/M7-3; 由此可见, 内酰胺化是罗库溴铵的主要代谢途径。值得注意的是, 在形成内酰胺代谢产物后, 原来的碱性胺基变为中性的酰胺, 在酸性流动相体系下, 内酰胺代谢产物相对于未内酰胺化的物质色谱保留时间会有明显延长, 这种色谱保留的变化特点可以帮助发现可能的内酰胺化代谢产物。此类代谢产物的色谱行为特征, 在本实验室对靶向抗肿瘤药物吡咯替尼的人体代谢产物研究中已有报道[17]。
M6-1/M6-2/M6-3是结合在药物不同官能团位置上的羟基化代谢产物, 互为同分异构体, 通过质谱无法确定其准确代谢位点。M8为乙酰化代谢产物, 推测由N-乙酰转移酶代谢产生。
转运体研究结果显示, 罗库溴铵是肝脏转运体MATE1、OATP1B1、OATP1B3和OCT1的底物, 这同文献报道的其主要通过肝脏清除的方式比较吻合。罗库溴铵为季铵盐阳离子型药物, 极性较大, 游离碱分子量为529.40, 根据类药性性质, 其具有较低的渗透性, 很难通过被动扩散透过细胞膜; 同时其较大的分子量增加了疏水性基团, 导致溶解度降低, 不利于通过肾脏清除, 而更倾向于通过肝脏清除。罗库溴铵可分别通过电荷识别肝细胞基底膜上的有机阳离子转运体OCT1, 通过其他方式(推测可能含有一定的疏水区域蛋白结合位点) 识别有机阴离子转运多肽OATP1B1和OATP1B3被摄取进入肝脏, 之后再通过肝细胞微管膜上的多药及毒素外排转运蛋白MATE1排泄至胆汁中。上述转运机制说明, MATE1不仅可以同OCT1, 也可以同OATP1B1与OATP1B3协同转运有机阳离子化合物罗库溴铵, 进行肝脏的摄取和胆汁的排泄。此外, 在临床联合用药时, 需关注相关转运体介导的药物相互作用。
作者贡献: 周爱南负责实验方案设计与实施和论文撰写; 郭子涛负责转运体实验; 陈佳骏、罗运权和谭波负责人体胆汁样本的采集和审核; 刁星星负责提供仪器设备和使用指导; 钟大放负责实验指导、监督及论文审阅。
利益冲突: 所有作者均声明不存在利益冲突。
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2022年第57卷第8期
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doi: 10.16438/j.0513-4870.2022-0583
  • 接收时间：2022-05-12
  • 首发时间：2025-12-23
  • 出版时间：2022-08-12
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  • 收稿日期：2022-05-12
  • 修回日期：2022-06-08
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    1.中国科学院上海药物研究所, 上海 201203
    2.上海中医药大学附属曙光医院, 上海 201203

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2种不同金属材料的力学参数
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Number of
species		 占总种数比例
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total species (%)		 属
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Number of
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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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