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Article(id=1208489268897493579, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1208489266397692345, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2021-0835, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1622822400000, receivedDateStr=2021-06-05, revisedDate=1632412800000, revisedDateStr=2021-09-24, acceptedDate=null, acceptedDateStr=null, onlineDate=1766055894349, onlineDateStr=2025-12-18, pubDate=1639238400000, pubDateStr=2021-12-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1766055894349, onlineIssueDateStr=2025-12-18, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1766055894349, creator=13701087609, updateTime=1766055894349, updator=13701087609, issue=Issue{id=1208489266397692345, tenantId=1146029695717560320, journalId=1189982191388893191, year='2021', volume='56', issue='12', pageStart='3203', pageEnd='3554', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1766055893754, creator=13701087609, updateTime=1766136983434, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1208829381217227030, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1208489266397692345, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1208829381217227031, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1208489266397692345, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=3518, endPage=3525, ext={EN=ArticleExt(id=1208489269744743009, articleId=1208489268897493579, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Pharmacokinetics of the main components differing between Ligustri Lucidi Fructus and its wine-steamed product, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

A quantitative analysis method for ten principal components (phenylethanol, iridoids and triterpenes) of raw Ligustri Lucidi Fructus and its wine-steamed product was developed using liquid chromatography tandem triple quadrupole mass spectrometry (LC-QQQ-MS) to study their pharmacokinetic behavior in vivo. The results of methodological investigation were in accord with the criteria of biological analysis. After a single administration to rats of the water extracts of Ligustri Lucidi Fructus and its wine-steamed product, the plasma concentration of each component at different time points was measured and the pharmacokinetic parameters were determined. The AUC0-24 h and Cmax of the phenylethanol components (salidroside, tyrosol, hydroxytyrosol) were the greatest, suggesting that these components are the main pharmacological substances of Ligustri Lucidi Fructus. In addition, the tmax values of the eight major components were even lower with administration of the wine-steamed product, suggesting that these components are rapidly absorbed. However, the tmax values of specnuezhenide and oleanolic acid were greater with administration of the wine-steamed product, indicating that these two components were more slowly absorbed. A secondary peak phenomenon of tyrosol and hydroxytyrosol were observed in two sample groups, whereas the secondary peak phenomenon of salidroside occurred only with the wine-steamed product. This result suggests that the effect of wine-steamed product could persist for a long period. Meanwhile, the relative bioavailability of specnuezhenide and oleanolic acid was greater than 100% with administration of the wine-steamed product, consistent with the Traditional Chinese Medicine theory of the wine-steamed product being more effective than the raw material. The results reveal the different pharmacokinetic parameters and relative bioavailability of each component of Ligustri Lucidi Fructus and its wine-steamed product, and also demonstrate the variation and correlation of various components in vivo and in vitro, providing an experimental basis for the selection of quality control indexes, mechanisms of processing and the metabolic rule in vivo of Ligustri Lucidi Fructus. These experiments were approved by the Ethics Committee of Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medicine Science.

, correspAuthors=Chun LI, Zhi-min WANG, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2021 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=Xin JI, Xiao-qian LIU, Lu GAO, Su-ping XIAO, Yao-hua LIANG, Chun LI, Zhi-min WANG), CN=ArticleExt(id=1208489271636374259, articleId=1208489268897493579, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=基于女贞子和酒女贞子中主要差异性成分的体内药代动力学研究, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

针对女贞子和酒女贞子中的10个主要差异性成分建立定量分析方法, 研究女贞子和酒女贞子分别给药后大鼠体内这10个成分(苯乙醇类、环烯醚萜类和三萜类) 的药代动力学行为。本研究利用LC-QQQ-MS技术建立了10个成分的定量分析方法, 方法学考察结果均符合生物样本分析要求。之后利用该方法检测了大鼠单次给药(同批次女贞子和酒女贞子水提物) 后不同时间点血浆中的各成分浓度, 计算了药物的药代动力学参数, 构建了各成分的药-时曲线。分析药代动力学参数发现, 苯乙醇类成分(红景天苷、酪醇、羟基酪醇) 在两种样本中的AUC0-24 h和Cmax均较大, 说明该类成分为女贞子类样本的主要药效物质。此外, 其中8种体外主要差异性成分的tmax值在酒女贞子给药条件时更小, 说明这些成分在酒女贞子给药后起效更快; 而另外2种成分—特女贞苷和齐墩果酸的tmax值则在酒女贞子给药时更大, 说明这两类成分在酒女贞子给药环境下有缓释、长效的特征。观察各成分药-时曲线发现, 酪醇和羟基酪醇在两组样本中均有二次达峰现象, 但红景天苷只在酒女贞子中有二次达峰, 该现象进一步提示酒女贞子给药后发挥作用更持久。另外, 通过计算发现, 酒女贞子给药条件下特女贞苷和齐墩果酸的相对生物利用度都大于100%, 进一步验证了“女贞子酒制增效”的中医理论。本文不仅明确了体外有差异的10种成分在不同给药组的药代参数及相对生物利用度的差异, 而且揭示了各类成分在体内外的变化规律及其关联性, 为女贞子和酒女贞子质控指标的选择以及炮制机制、体内代谢规律的深入研究提供了实验依据。本实验获得中国中医科学院中医基础理论研究所伦理委员会批准。

, correspAuthors=李春, 王智民, authorNote=null, correspAuthorsNote=
*李春, Tel: 86-10-84014128, E-mail:
王智民, E-mail:
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China J Chin Mater Med (中国中药杂志), 2021, 46: 1168-1178, articleTitle=Qualitative and quantitative analysis on triterpenoids in Ligustri Lucidi Fructus, refAbstract=null), Reference(id=1208489283711775458, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208489268897493579, doi=null, pmid=null, pmcid=null, year=2018, volume=43, issue=null, pageStart=4862, pageEnd=4868, url=https://www.cnki.com.cn/Article/CJFDTOTAL-ZSHK201403007.htm, language=null, rfNumber=[22], rfOrder=21, authorNames=null, journalName=China J Chin Mater Med (中国中药杂志), refType=null, unstructuredReference=Ji X, Liu XQ, Li C, et al. Content change of main components in processed Ligustrum lucidum fruits of different processing time and their characteristic quality standard based on UPLC technology[J]. China J Chin Mater Med (中国中药杂志), 2018, 43: 4862-4868, articleTitle=Content change of main components in processed Ligustrum lucidum fruits of different processing time and their characteristic quality standard based on UPLC technology, refAbstract=null)], funds=[Fund(id=1208489280079507890, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208489268897493579, awardId=ZYBZH-C-JL-26, language=CN, fundingSource=国家中药标准化项目(ZYBZH-C-JL-26), fundOrder=null, country=null), Fund(id=1208489280175976892, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208489268897493579, awardId=2018ZX09721004-001, language=CN, fundingSource=国家科技重大专项_重大新药创制项目(2018ZX09721004-001), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1208489272059998984, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208489268897493579, xref=null, ext=[AuthorCompanyExt(id=1208489272068387593, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208489268897493579, companyId=1208489272059998984, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1. 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China National of Traditional & Herbal Medicine Co., Ltd., Beijing 102600, China), AuthorCompanyExt(id=1208489273272152868, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208489268897493579, companyId=1208489273255375650, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=3.中国中药有限公司, 北京 102600)])], figs=[ArticleFig(id=1208489278351454438, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208489268897493579, language=EN, label=null, caption=null, figureFileSmall=IkjjMe+Txe++k9L1rYDk8w==, figureFileBig=9bMH8aYCaa10Pv0Dy30mmw==, tableContent=null), ArticleFig(id=1208489278431146226, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208489268897493579, language=CN, label=Figure 1, caption= MRM of 11 components in rat plasma. a: Hydroxytyrosol; b: Tyrosol; c: Salidroside; d: Echinacoside; e: Acteoside; f: Specnuezhenide; g: Oleuropein; h: G13; i: Oleonuezhenide; j: Oleanolic acid; k: Geniposide , figureFileSmall=IkjjMe+Txe++k9L1rYDk8w==, figureFileBig=9bMH8aYCaa10Pv0Dy30mmw==, tableContent=null), ArticleFig(id=1208489278754107672, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208489268897493579, language=EN, label=null, caption=null, figureFileSmall=12vFR2KuY3mbUhUMFWjWGg==, figureFileBig=hf1Nt0CvQT2+PQ++LduXag==, tableContent=null), ArticleFig(id=1208489278934462761, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208489268897493579, language=CN, label=Figure 2, caption= Drug-time curve of 10 components of Ligustri Lucidi Fructus and wine-steamed product after single administration (<i>n</i> = 6, <span class="mag-xml-inline-formula">$ \overline{x} $</span> ± <i>s</i>). a: Hydroxytyrosol; b: Tyrosol; c: Salidroside; d: Echinacoside; e: Acteoside; f: Specnuezhenide; g: Oleuropein; h: G13; i: Oleonuezhenide; j: Oleanolic acid , figureFileSmall=12vFR2KuY3mbUhUMFWjWGg==, figureFileBig=hf1Nt0CvQT2+PQ++LduXag==, tableContent=null), ArticleFig(id=1208489279039320374, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208489268897493579, language=EN, label=null, caption=null, figureFileSmall=5AfN747dB5aYxDV9LITfnw==, figureFileBig=tkY9zzL7rcurhEV5iIk4Xg==, tableContent=null), ArticleFig(id=1208489279186121035, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208489268897493579, language=CN, label=Figure 3, caption= Conversion mechanism of salidroside and other components in the preparation of wine-steamed Ligustri Lucidi Fructus , figureFileSmall=5AfN747dB5aYxDV9LITfnw==, figureFileBig=tkY9zzL7rcurhEV5iIk4Xg==, tableContent=null), ArticleFig(id=1208489279328727384, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208489268897493579, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
No.CompoundMode of ionizationParent ion m/zDaughter ion m/zFragmentor/VCollision energy/V
1HydroxytyrosolESI+1771771500
2TyrosolESI+1931931500
3SalidrosideESI+3233231200
4EchinacosideESI-7857851200
5ActeosideESI-62316120025
6SpecnuezhenideESI-68552311012
7OleuropeinESI-53927518018
8G13ESI+1 0951 09518535
9OleonuezhenideESI+1 0951 09518520
10Oleanolic acidESI-45545511214
11GeniposideESI+4114111650
), ArticleFig(id=1208489279513276777, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208489268897493579, language=CN, label=Table 1, caption=

Mass spectrometry parameters of 11 components

, figureFileSmall=null, figureFileBig=null, tableContent=
No.CompoundMode of ionizationParent ion m/zDaughter ion m/zFragmentor/VCollision energy/V
1HydroxytyrosolESI+1771771500
2TyrosolESI+1931931500
3SalidrosideESI+3233231200
4EchinacosideESI-7857851200
5ActeosideESI-62316120025
6SpecnuezhenideESI-68552311012
7OleuropeinESI-53927518018
8G13ESI+1 0951 09518535
9OleonuezhenideESI+1 0951 09518520
10Oleanolic acidESI-45545511214
11GeniposideESI+4114111650
), ArticleFig(id=1208489279618134391, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208489268897493579, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
ComponentLinear relationr2Linear range/ngLOQ/ng
HydroxytyrosolY = 17.384 X - 0.000 31.000 04.6-18 4002.300
TyrosolY = 136.14 X + 0.060.999 65.75-23 0002.875
SalidrosideY = 10 134 X - 1.327 90.999 53.35-13 4001.675
EchinacosideY = 11.643 X + 0.002 90.999 36-24 0003.000
ActeosideY = 68.093 X + 0.012 60.999 53.4-13 6001.700
SpecnuezhenideY = 493.53 X - 0.023 91.000 050.6-202 40025.300
OleuropeinY = 277.16 X + 0.007 80.999 82.55-10 2001.275
G13Y = 8.551 1 X - 0.001 90.999 47.85-31 4003.925
OleonuezhenideY = 4.542 8 X + 0.002 70.999 22.65-10 6001.325
Oleanolic acidY = 69.614 X + 0.097 20.998 016.9-67 6008.450
), ArticleFig(id=1208489279714603395, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208489268897493579, language=CN, label=Table 2, caption=

Regression equations, linear ranges and limits of quantification (LOQ) for 10 components in plasma

, figureFileSmall=null, figureFileBig=null, tableContent=
ComponentLinear relationr2Linear range/ngLOQ/ng
HydroxytyrosolY = 17.384 X - 0.000 31.000 04.6-18 4002.300
TyrosolY = 136.14 X + 0.060.999 65.75-23 0002.875
SalidrosideY = 10 134 X - 1.327 90.999 53.35-13 4001.675
EchinacosideY = 11.643 X + 0.002 90.999 36-24 0003.000
ActeosideY = 68.093 X + 0.012 60.999 53.4-13 6001.700
SpecnuezhenideY = 493.53 X - 0.023 91.000 050.6-202 40025.300
OleuropeinY = 277.16 X + 0.007 80.999 82.55-10 2001.275
G13Y = 8.551 1 X - 0.001 90.999 47.85-31 4003.925
OleonuezhenideY = 4.542 8 X + 0.002 70.999 22.65-10 6001.325
Oleanolic acidY = 69.614 X + 0.097 20.998 016.9-67 6008.450
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PK parameterGroupHydroxytyrosolTyrosolSalidrosideEchinacosideActeoside
Dose / mg·kg-110.250.000 108.3110.305.15
20.590.000 0224.2510.946.43
tmax / h11.36 ± 1.443.75 ± 2.790.83 ± 0.411.22 ± 1.521.097 ± 1.48
20.28 ± 0.191.75 ± 1.300.75 ± 0.420.65 ± 0.600.49 ± 0.43
Cmax /ng·mL-1120 924.23 ± 39.502 717.77 ± 17.30*1 148.89 ± 18.70**1 134.40 ± 34.50*489.64 ± 54.70
230 974.99 ± 32.004 016.44 ± 33.801 979.55 ± 27.00739.28 ± 30.80864.80 ± 53.80
AUC0-24 h / ng·h·mL-11160 413.95 ± 22.7017 621.51 ± 20.00**6 052.58 ± 15.10**6 406.98 ± 49.10*1 647.98 ± 86.30
2195 609.34 ± 16.2027 615.037 ± 25.809 366.93 ± 10.102 635.36 ± 61.301 867.20 ± 44.10
AUC0-∞ / ng·h·mL-11275 735.85 ± 59.6026 375.74 ± 52.7035 410.25 ± 94.207 083.48 ± 53.601 770.98 ± 93.50
2346 846.48 ± 35.6041 264.62 ± 82.6029 089.91 ± 94.603 150.86 ± 49.202 436.16 ± 67.00
MRT0-24 h / h19.20 ± 1.0968.58 ± 1.987.68 ± 0.69**8.58 ± 1.984.85 ± 2.10
29.22 ± 0.648.11 ± 1.706.02 ± 0.468.58 ± 1.985.15 ± 1.65
PK parameterGroupSpecnuezhenideOleuropeinG13OleonuezhenideOleanolic acid
Dose / mg·kg-11150.806.1434.3625.6163.33
2106.953.7725.3810.6659.57
tmax / h12.097 ± 2.361.33 ± 1.460.76 ± 0.790.78 ± 0.731.31 ± 1.49
22.42 ± 2.150.89 ± 1.530.49 ± 0.430.40 ± 0.352.69 ± 2.02
Cmax /ng·mL-11428.084 ± 106.1089.76 ± 45.601 859.23 ± 45.903 965.62 ± 53.508 307.49 ± 108.50
2189.29 ± 107.10122.019 ± 135.602 098.59 ± 38.704 142.97 ± 36.8012 512.97 ± 146.60
AUC0-24 h / ng·h·mL-111 857.50 ± 54.30640.73 ± 29.70**14 719.41 ± 55.3017 245.018 ± 86.5012 003.050 ± 59.30
21 477.53 ± 12.70123.94 ± 53.009 428.84 ± 33.606 914.25 ± 44.4027 313.11 ± 127.20
AUC0-∞ / ng·h·mL-1110 776.84 ± 82.90828.16 ± 39.1020 827.51 ± 77.0022 316.55 ± 95.4012 136.83 ± 59.50
218 591.94 ± 137.60133.76 ± 47.0014 384.45 ± 40.209 165.69 ± 52.5027 425.60 ± 127.50
MRT0-24 h / h110.30 ± 1.9711.20 ± 2.24**10.61 ± 1.917.32 ± 2.233.66 ± 1.54
211.45 ± 0.716.47 ± 1.368.68 ± 1.305.34 ± 1.643.97 ± 0.99
), ArticleFig(id=1208489279911735706, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208489268897493579, language=CN, label=Table 3, caption=

PK parameters of 10 components of Ligustri Lucidi Fructus and wine-steamed product after single administration. n = 6, $ \overline{x} $ ± s. *P < 0.05, **P < 0.01 vs wine-steamed product. Group 1 represents the Ligustri Lucidi Fructus Group; Group 2 represents wine-steamed Ligustri Lucidi Fructus Group

, figureFileSmall=null, figureFileBig=null, tableContent=
PK parameterGroupHydroxytyrosolTyrosolSalidrosideEchinacosideActeoside
Dose / mg·kg-110.250.000 108.3110.305.15
20.590.000 0224.2510.946.43
tmax / h11.36 ± 1.443.75 ± 2.790.83 ± 0.411.22 ± 1.521.097 ± 1.48
20.28 ± 0.191.75 ± 1.300.75 ± 0.420.65 ± 0.600.49 ± 0.43
Cmax /ng·mL-1120 924.23 ± 39.502 717.77 ± 17.30*1 148.89 ± 18.70**1 134.40 ± 34.50*489.64 ± 54.70
230 974.99 ± 32.004 016.44 ± 33.801 979.55 ± 27.00739.28 ± 30.80864.80 ± 53.80
AUC0-24 h / ng·h·mL-11160 413.95 ± 22.7017 621.51 ± 20.00**6 052.58 ± 15.10**6 406.98 ± 49.10*1 647.98 ± 86.30
2195 609.34 ± 16.2027 615.037 ± 25.809 366.93 ± 10.102 635.36 ± 61.301 867.20 ± 44.10
AUC0-∞ / ng·h·mL-11275 735.85 ± 59.6026 375.74 ± 52.7035 410.25 ± 94.207 083.48 ± 53.601 770.98 ± 93.50
2346 846.48 ± 35.6041 264.62 ± 82.6029 089.91 ± 94.603 150.86 ± 49.202 436.16 ± 67.00
MRT0-24 h / h19.20 ± 1.0968.58 ± 1.987.68 ± 0.69**8.58 ± 1.984.85 ± 2.10
29.22 ± 0.648.11 ± 1.706.02 ± 0.468.58 ± 1.985.15 ± 1.65
PK parameterGroupSpecnuezhenideOleuropeinG13OleonuezhenideOleanolic acid
Dose / mg·kg-11150.806.1434.3625.6163.33
2106.953.7725.3810.6659.57
tmax / h12.097 ± 2.361.33 ± 1.460.76 ± 0.790.78 ± 0.731.31 ± 1.49
22.42 ± 2.150.89 ± 1.530.49 ± 0.430.40 ± 0.352.69 ± 2.02
Cmax /ng·mL-11428.084 ± 106.1089.76 ± 45.601 859.23 ± 45.903 965.62 ± 53.508 307.49 ± 108.50
2189.29 ± 107.10122.019 ± 135.602 098.59 ± 38.704 142.97 ± 36.8012 512.97 ± 146.60
AUC0-24 h / ng·h·mL-111 857.50 ± 54.30640.73 ± 29.70**14 719.41 ± 55.3017 245.018 ± 86.5012 003.050 ± 59.30
21 477.53 ± 12.70123.94 ± 53.009 428.84 ± 33.606 914.25 ± 44.4027 313.11 ± 127.20
AUC0-∞ / ng·h·mL-1110 776.84 ± 82.90828.16 ± 39.1020 827.51 ± 77.0022 316.55 ± 95.4012 136.83 ± 59.50
218 591.94 ± 137.60133.76 ± 47.0014 384.45 ± 40.209 165.69 ± 52.5027 425.60 ± 127.50
MRT0-24 h / h110.30 ± 1.9711.20 ± 2.24**10.61 ± 1.917.32 ± 2.233.66 ± 1.54
211.45 ± 0.716.47 ± 1.368.68 ± 1.305.34 ± 1.643.97 ± 0.99
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基于女贞子和酒女贞子中主要差异性成分的体内药代动力学研究
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纪鑫 1 , 刘晓谦 1 , 高陆 2 , 肖苏萍 3 , 梁曜华 1 , 李春 1, * , 王智民 1, *
药学学报 | 研究论文 2021,56(12): 3518-3525
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药学学报 | 研究论文 2021, 56(12): 3518-3525
基于女贞子和酒女贞子中主要差异性成分的体内药代动力学研究
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纪鑫1, 刘晓谦1, 高陆2, 肖苏萍3, 梁曜华1, 李春1, * , 王智民1, *
作者信息
  • 1.中国中医科学院中药研究所, 中药质量控制技术国家工程实验室, 北京 100700
  • 2.修正药业集团股份有限公司, 吉林 长春 130012
  • 3.中国中药有限公司, 北京 102600

通讯作者:

*李春, Tel: 86-10-84014128, E-mail:
王智民, E-mail:
Pharmacokinetics of the main components differing between Ligustri Lucidi Fructus and its wine-steamed product
Xin JI1, Xiao-qian LIU1, Lu GAO2, Su-ping XIAO3, Yao-hua LIANG1, Chun LI1, * , Zhi-min WANG1, *
Affiliations
  • 1. Institute of Chinese Materia Medica, National Engineering Laboratory for Quality Control Technology of Chinese Herbal Medicines, China Academy of Chinese Medical Sciences, Beijing 100700, China
  • 2. Xiuzheng Pharmaceutical Group Co., Ltd., Changchun 130012, China
  • 3. China National of Traditional & Herbal Medicine Co., Ltd., Beijing 102600, China
出版时间: 2021-12-12 doi: 10.16438/j.0513-4870.2021-0835
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摘要
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针对女贞子和酒女贞子中的10个主要差异性成分建立定量分析方法, 研究女贞子和酒女贞子分别给药后大鼠体内这10个成分(苯乙醇类、环烯醚萜类和三萜类) 的药代动力学行为。本研究利用LC-QQQ-MS技术建立了10个成分的定量分析方法, 方法学考察结果均符合生物样本分析要求。之后利用该方法检测了大鼠单次给药(同批次女贞子和酒女贞子水提物) 后不同时间点血浆中的各成分浓度, 计算了药物的药代动力学参数, 构建了各成分的药-时曲线。分析药代动力学参数发现, 苯乙醇类成分(红景天苷、酪醇、羟基酪醇) 在两种样本中的AUC0-24 h和Cmax均较大, 说明该类成分为女贞子类样本的主要药效物质。此外, 其中8种体外主要差异性成分的tmax值在酒女贞子给药条件时更小, 说明这些成分在酒女贞子给药后起效更快; 而另外2种成分—特女贞苷和齐墩果酸的tmax值则在酒女贞子给药时更大, 说明这两类成分在酒女贞子给药环境下有缓释、长效的特征。观察各成分药-时曲线发现, 酪醇和羟基酪醇在两组样本中均有二次达峰现象, 但红景天苷只在酒女贞子中有二次达峰, 该现象进一步提示酒女贞子给药后发挥作用更持久。另外, 通过计算发现, 酒女贞子给药条件下特女贞苷和齐墩果酸的相对生物利用度都大于100%, 进一步验证了“女贞子酒制增效”的中医理论。本文不仅明确了体外有差异的10种成分在不同给药组的药代参数及相对生物利用度的差异, 而且揭示了各类成分在体内外的变化规律及其关联性, 为女贞子和酒女贞子质控指标的选择以及炮制机制、体内代谢规律的深入研究提供了实验依据。本实验获得中国中医科学院中医基础理论研究所伦理委员会批准。

女贞子  /  酒女贞子  /  差异性成分  /  药代动力学  /  液相色谱串联三重四极杆质谱

A quantitative analysis method for ten principal components (phenylethanol, iridoids and triterpenes) of raw Ligustri Lucidi Fructus and its wine-steamed product was developed using liquid chromatography tandem triple quadrupole mass spectrometry (LC-QQQ-MS) to study their pharmacokinetic behavior in vivo. The results of methodological investigation were in accord with the criteria of biological analysis. After a single administration to rats of the water extracts of Ligustri Lucidi Fructus and its wine-steamed product, the plasma concentration of each component at different time points was measured and the pharmacokinetic parameters were determined. The AUC0-24 h and Cmax of the phenylethanol components (salidroside, tyrosol, hydroxytyrosol) were the greatest, suggesting that these components are the main pharmacological substances of Ligustri Lucidi Fructus. In addition, the tmax values of the eight major components were even lower with administration of the wine-steamed product, suggesting that these components are rapidly absorbed. However, the tmax values of specnuezhenide and oleanolic acid were greater with administration of the wine-steamed product, indicating that these two components were more slowly absorbed. A secondary peak phenomenon of tyrosol and hydroxytyrosol were observed in two sample groups, whereas the secondary peak phenomenon of salidroside occurred only with the wine-steamed product. This result suggests that the effect of wine-steamed product could persist for a long period. Meanwhile, the relative bioavailability of specnuezhenide and oleanolic acid was greater than 100% with administration of the wine-steamed product, consistent with the Traditional Chinese Medicine theory of the wine-steamed product being more effective than the raw material. The results reveal the different pharmacokinetic parameters and relative bioavailability of each component of Ligustri Lucidi Fructus and its wine-steamed product, and also demonstrate the variation and correlation of various components in vivo and in vitro, providing an experimental basis for the selection of quality control indexes, mechanisms of processing and the metabolic rule in vivo of Ligustri Lucidi Fructus. These experiments were approved by the Ethics Committee of Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medicine Science.

Ligustri Lucidi Fructus  /  wine-steamed Ligustri Lucidi Fructus  /  differential component  /  pharmacokinetics  /  liquid chromatography tandem triple quadrupole mass spectrometry
纪鑫, 刘晓谦, 高陆, 肖苏萍, 梁曜华, 李春, 王智民. 基于女贞子和酒女贞子中主要差异性成分的体内药代动力学研究. 药学学报, 2021 , 56 (12) : 3518 -3525 . DOI: 10.16438/j.0513-4870.2021-0835
Xin JI, Xiao-qian LIU, Lu GAO, Su-ping XIAO, Yao-hua LIANG, Chun LI, Zhi-min WANG. Pharmacokinetics of the main components differing between Ligustri Lucidi Fructus and its wine-steamed product[J]. Acta Pharmaceutica Sinica, 2021 , 56 (12) : 3518 -3525 . DOI: 10.16438/j.0513-4870.2021-0835
正文
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女贞子为木犀科植物女贞(Ligustrum lucidum Ait.) 的干燥成熟果实, 具有滋补肝肾、明目乌发的功效, 用于肝肾阴虚、眩晕耳鸣、腰膝酸软、须发早白、目暗不明、内热消渴、骨蒸潮热[1]。现阶段对女贞子的研究认为, 苯乙醇类、环烯醚萜类和三萜类成分是女贞子发挥药效的主要物质基础[2-14]。现代药理学研究表明, 绝大多数化学成分只有入血并维持在一定浓度之上才能发挥药效, 但是至今女贞子中的主要成分在体内发挥药效的过程尚不明确。目前只有零星的文献单独报道了女贞子或酒女贞子中化学成分的体内过程[15, 16], 以及部分单体成分如特女贞苷、红景天苷、橄榄苦苷的体内过程[17-19], 但是, 基于同批次女贞子和酒女贞子中化学成分差异性分析, 并以二者的主要差异性成分为研究对象, 深入探究其水提取物整体给药后体外主要差异性成分的体内过程尚未见报道。
前期研究表明, 女贞子在炮制成酒女贞子的过程中化学成分发生转化, 环烯醚萜类成分(特女贞苷、橄榄苦苷、女贞苷G13和oleonuezhenide) 和苯乙醇苷类(松果菊糖苷、毛蕊花糖苷和红景天苷) 在加热和黄酒的共同作用下发生水解, 产生苯乙醇类化合物片段(酪醇、羟基酪醇和红景天苷), 因此女贞子炮制后, 环烯醚萜类成分含量明显下降, 而苯乙醇类含量显著上升; 比较特殊的是, 红景天苷既是女贞子中固有的成分可进一步水解产生酪醇, 同时又是多种环烯醚萜类成分水解产生的主要水解产物[20-22]。因此, 为进一步探究同批次女贞子和酒女贞子中存在显著差异的化学成分在体内的代谢特征, 本文结合中医药临床服药特点, 按照中药临床煎煮方法制备了同批次女贞子和酒女贞子的水提取物, 利用建立的液相色谱串联三重四极杆质谱(LC-QQQ-MS) 方法检测单次灌胃给药后不同时间点大鼠血浆中3大类成分(环烯醚萜类、苯乙醇类和三萜类) 中的10个代表性化合物(在女贞子和同批次酒女贞子中存在显著性差异) 的血药浓度, 计算其药代动力学参数, 描述不同成分在体内的药-时变化规律, 深入分析各化学成分在体内外变化规律的相关性, 为阐明女贞子的药效物质基础, 进一步探究其炮制机制及体内外物质代谢转化规律, 并制定女贞子药材和饮片适宜的质量控制标准提供依据。
材料与方法
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材料与仪器  女贞子(批号: NZ-180115-SC, 产地四川, 购于河北安国药材市场), 酒女贞子(批号: JNZ-180115-SC, 产地四川, 由批号为NZ-180115-SC的女贞子炮制加工而成, 炮制过程由祁澳中药饮片有限公司实施), 经中国中医科学院中药研究所李春研究员鉴定为木犀科植物女贞(Ligustrum lucidum Ait.) 的干燥成熟果实或其炮制品。
对照品酪醇(批号Q-042-150730)、羟基酪醇(批号Q-079-160114)、红景天苷(批号B20504)、松果菊糖苷(批号wkq16061701)、毛蕊花糖苷(批号wkq16062004)、特女贞苷(批号wkq18022805)、橄榄苦苷(批号wkq17080413)、女贞苷G13 (批号wkq17011608) 均购自四川维克奇生物科技有限公司, 经HPLC检测、面积归一化法计算纯度≥ 98%; oleonuezhenide (批号180515, 纯度≥ 95%) 购自成都植标化纯生物技术有限公司。齐墩果酸(批号110709-201808, 含量≥ 99.9%) 和熊果酸(批号110742-201622, 含量≥ 99.9%) 购自中国食品药品检定研究院。京尼平苷(批号16052902, 纯度≥ 98%) 购自北京赛百草科技有限公司。肝素钠购自Solarbio公司。质谱级甲醇和乙腈(Fisher公司, 美国), 水为屈臣氏纯净水, 色谱级甲酸(ROE SCIENTIFIC INC., 美国), 氯化钠注射液(石家庄四药有限公司)。1.5 mL离心管(肝素钠溶液抗凝处理), 毛细管(均匀截3段, 采血前肝素钠溶液抗凝处理), 采血针。
Agilent 1200液相-质谱联用仪(包括Agilent 1200超高效液相色谱, 6410B三重四级杆串联质谱, 电喷雾离子源); 氮吹干燥仪(HENGAO T & D公司), 氮气发生器(北京中兴汇利科技发展有限公司); 1/10万分析天平(XS205型, 瑞士, 梅特勒—托利多仪器有限公司); Multifuge X1 R高速离心机(美国, Thermo公司); 涡旋仪(德国, IKA公司), 超声波清洗器(KQ-250DB, 昆山市超声仪器有限公司)。
动物  清洁级雄性SD大鼠[实验动物许可证编号为SCXK (京) 2016-0011], 18只, 体重约220~240 g。
色谱条件   Acquity UPLC® BEH C18色谱柱(2.1 mm × 50 mm, 1.7 μm); 流动相: 乙腈(A)-0.2%甲酸水(B), 梯度洗脱(0~2 min, 3% A; 2~6 min, 3%~9% A; 6~11 min, 9%~12% A; 11~16 min, 12%~16% A; 16~20 min, 16% A; 20~26 min, 16%~23% A; 26~32 min, 23%~35% A; 32~35 min, 35% A; 35~35.01 min, 35%~90% A; 35.01~40 min, 90%~95% A; 40~43 min, 95% A); 流速: 0.2 mL·min-1; 柱温: 30 ℃; 进样量: 2 μL。
质谱条件  离子源: 电喷雾离子源; 检测方式: 多反应监测(MRM); 毛细管电压: 4.0 kV; 雾化气流速: 10.0 L·min-1; 脱溶剂气流速: 30.0 L·min-1; 脱溶剂管温度: 325 ℃; 加热模块温度: 325 ℃; Dwell: 200; 正负离子交替检测模式: Delta EMV (+): 200 V; Delta EMV (-): 200 V。采集模式、监测离子对(m/z) 和其他参数见表 1。
混合对照品溶液的配制  精密称取酪醇、羟基酪醇、红景天苷、松果菊糖苷、毛蕊花糖苷、特女贞苷、橄榄苦苷、女贞苷G13、oleonuezhenide和齐墩果酸各对照品适量, 加甲醇溶解配制成浓度分别为18.4、23.0、13.4、24.0、13.6、202.4、10.2、31.4、10.6和67.6 μg·mL-1的混合对照品溶液, 记为1#溶液。取1#溶液逐级稀释2、4、20、100、200、1 000、2 000和4 000倍配制得到不同浓度的2#~9#混合对照品溶液, 备用。
精密称取京尼平苷对照品适量, 加乙腈溶解后定容至50 mL量瓶中, 得到浓度为0.047 mg·mL-1的母液。取该母液0.1 mL稀释并定容至50 mL乙腈中, 得到浓度为94 ng·mL-1的对照品溶液, 作为内标溶液。
供试品溶液的制备  分别取女贞子和酒女贞子粗粉各400 g, 加水回流提取2次, 每次1 h, 加水量分别为样品量的10倍和6倍, 过滤后合并两次滤液, 分别浓缩成每毫升含样品量1.6 g的浓缩液。取83 mL浓缩液, 加水稀释至243 mL, 最终配成浓度为0.546 5 g·mL-1的溶液。
QC样本的制备  精密吸取高、中、低三个不同浓度的混标溶液各100 μL后, 置于1.5 mL离心管中, 控温40 ℃氮气吹干后, 加入空白血浆基质100 μL, 涡旋离心约1 min后混匀, 得到高、中、低三个不同浓度的QC样本, 置于-80 ℃条件下保存备用。
血样处理方法  将血样置于肝素钠预处理的离心管中, 振揺离心管使抗凝剂与血样充分接触, 密封置于4 ℃冰浴。4 ℃温度下离心10 min (转速5 000 r·min-1), 分离上层含药血浆(空白血样采用同样方法离心制备空白血浆), 离心后的血浆在-80 ℃条件下保存待用。
内标血样处理方法  血样室温融化混匀后精密吸取100 μL, 置于干净1.5 mL离心管中, 加入乙腈(含京尼平苷内标) 200 μL, 涡旋仪混匀1 min后, 14 800 r·min-1在室温下离心20 min, 吸取上清液100 μL于干净1.5 mL离心管中, 在40 ℃条件下控温氮气吹干, 以80%甲醇溶液复溶该样本, 涡旋2 min混匀后, 室温下14 800 r·min-1离心20 min后, 吸取上清液进样。
方法学考察
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专属性   取不同来源的大鼠空白血浆, 除不加内标溶液(等体积的乙腈代替) 外, 其余按“内标血样处理方法”项下操作, 进行LC-QQQ-MS检测分析, 通过对比空白血样、含药血样以及提取物配制成的溶液的质谱图, 记录选定的11种化学成分的MRM质谱图, 考察分析方法的特异性。
线性关系及定量限建立   精密吸取1#~9#混合对照品溶液各100 μL至1.5 mL离心管中, 40 ℃控温氮气吹干。分别精密吸取空白血浆至处理过的离心管中(100 μL), 涡旋1 min充分混匀后, 分别加入含内标的乙腈溶液200 μL, 涡旋1 min后, 常温下离心20 min (14 800 r·min-1)。按内标血样处理方法项下加内标离心后的步骤处理样本, 之后吸取上清液进样。以血浆中各对照品的质量X/ng与峰面积比值Y (A对照品/A内标) 做标准曲线, 拟合得到回归方程。以信噪比10作为定量限。
精密度   选择高、中、低3个不同浓度的QC样本, 分别精密吸取100 μL (每浓度5份, 共计15份) 于干净的1.5 mL离心管中, 精密加入内标溶液200 μL, 涡旋1 min后常温离心20 min (14 800 r·min-1), 按“内标血样处理方法”加内标离心后的步骤处理样本, 吸取上清液进样。各浓度样本1日之内检测6次, 连续测定6天, 记录各成分及内标峰面积, 计算日内精密度和日间精密度。
提取回收率及基质效应   选择高、中、低3个不同浓度的QC样本, 精密吸取100 μL (每浓度6份, 共计18份), 置于干净的1.5 mL离心管中, 精密加入内标溶液200 μL, 涡旋1 min后, 常温离心20 min (14 800 r·min-1) 得上清液。按内标血样处理方法项下加内标离心后的步骤处理样本, 之后吸取上清液进样。记录各成分色谱峰峰面积A。选择高、中、低3个不同浓度的混合对照品溶液, 精密吸取100 μL (每浓度6份, 共计18份) 置于干净的1.5 mL离心管中, 控温40 ℃氮气吹干, 备用。另取18个干净离心管, 分别精密加入空白血浆基质100 μL, 涡旋1 min混匀后, 精密加入内标溶液200 μL, 再涡旋1 min后, 常温离心20 min (14 800 r·min-1) 获得去除蛋白质的含内标的上清液, 按“内标血样处理方法”项下的方法, 精密吸取含内标的上清液100 μL至前文中氮气吹干后含有混合对照品的1.5 mL离心管中, 混匀后控温40 ℃氮气吹干后, 加80 %甲醇100 μL复溶, 涡旋2 min, 室温14 800 r·min-1离心20 min后, 吸取上清液进样, 记录各成分色谱峰峰面积。按照式1计算各成分的提取回收率。
$提取回收率{\rm{ = }}A/B \times 100\% $
式1中A代表不同浓度的QC样本经过处理后各成分的色谱峰峰面积, B代表不同浓度的混合对照品溶液干燥后加空白血浆复溶样本经过处理后各成分的色谱峰峰面积。
选择高、中、低3个不同浓度的混合对照品溶液, 精密吸取100 μL (每个浓度6份, 共计18份) 于干净的1.5 mL离心管中, 涡旋1 min混匀后, 加入内标溶液(乙腈) 200 μL, 再涡旋1 min后, 常温离心20 min (14 800 r·min-1), 按内标血样处理方法项下加内标离心后的步骤处理样本, 之后吸取上清液进样。记录各成分色谱峰峰面积C。按照式2计算各成分的基质效应。
$基质效应{\rm{ = }}B/C \times 100\% $
式2中B代表不同浓度的混合对照品溶液干燥后加空白血浆复溶样本经过处理后各成分的色谱峰峰面积, C代表混合对照品溶液经处理后各成分的色谱峰峰面积。
稳定性考察  取高、中、低3种不同浓度的QC样本(各平行3份), 按内标血样处理方法项下操作后, 分别进行以下4种稳定性考察: ① 4 ℃条件下各成分稳定性: 4 ℃下放置0、24和48 h的各成分峰面积; ②各成分室温稳定性: 室温下放置4 h后各成分峰面积; ③各成分的冻融稳定性: -80 ℃保存24 h反复冻融3次后各成分峰面积; ④各成分长期稳定性: -80 ℃保存15天后各成分峰面积, 计算各成分浓度。
药代动力学动物实验方法  大鼠常规适应性喂养3天, 于第3天下午称体重后, 按体重进行随机分组, 分为空白组、女贞子组和酒女贞子组(每组n = 6)。分组后禁食不禁水。第4天在取血前称量禁食后的体重。
以临床最大给药剂量12 g为基础, 根据人-大鼠剂量转换公式, 按照临床等效剂量的4倍计算大鼠给药量, 最终确定大鼠给药量为每百克体重0.56 g (按生药量计算)。女贞子和酒女贞子水提物浓缩液的灌胃剂量为每百克体重1 mL, 根据每只大鼠第4天禁食后的体重计算每只大鼠的给药体积, 按顺序灌胃给药。
每组大鼠分别于给药后0.083、0.25、0.5、1、1.5、2、4、6、8、12和24 h眼眶采血(4 h血样采集后大鼠给食、给水)。将血样样本置于肝素钠预处理的离心管中, 振揺混匀, 密封置于4 ℃冰浴。4 ℃温度下, 以5 000 r·min-1转速离心10 min, 取上清液, -80 ℃保存待用。所有动物实验过程和动物关怀均获得中国中医科学院中医基础理论研究所伦理委员会的批准。
数据处理  将含药血浆按照“内标血样处理方法”项下方法处理后进行LC-QQQ-MS检测分析, 分别记录不同样本各成分的峰面积, 以随行校正曲线计算血浆药物浓度。根据不同时间的血药浓度, 利用GraphPad Prism 7.00软件绘制各成分的药-时曲线。之后将血药浓度时间数据带入DAS 3.3药代统计学软件求算10种代表性成分在大鼠体内的各项药代动力学参数, 并用SPSS.23.0软件分析两组间10个代表性成分主要药代参数统计学差异。同时, 根据相对生物利用度= [(AUC0-24 h酒女贞子 / dose酒女贞子) / (AUC0-24 h女贞子 / dose女贞子)] × 100%, 进一步计算10个代表性成分的相对生物利用度。
结果
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1 方法学验证
1.1 专属性
11个成分的MRM图见图 1, 羟基酪醇、酪醇、红景天苷、松果菊糖苷、毛蕊花糖苷、特女贞苷、橄榄苦苷、女贞苷G13、oleonuezhenide、齐墩果酸及内标京尼平苷的色谱保留时间分别为13.8、5.1、9.7、18.2、21.8、24.0、28.2、32.0、32.3、42.0和14.1 min。干扰组分的响应低于LOQ响应的20%及内标响应的5%, 本实验的10种代表性体外差异成分及内标的峰形良好, 大鼠空白血浆中的内源性物质不干扰待测物和内标的定量分析, 本方法具有良好的专属性。
1.2 线性关系及定量限
10种女贞子和酒女贞子代表性体外差异成分及内标京尼平苷在大鼠血浆中的线性范围内线性良好, 结果见表 2。
1.3 精密度
10个成分的日内精密度RSD值在0.82%~9.94%之间, RE值在0.01%~16.77%之间; 日间精密度RSD值在0.56%~9.02%之间, RE值在0.06%~6.22%之间; 所有RSD值均不高于9.94%, RE值在标准范围之内均符合有关生物样品分析方法验证的要求, 提示所建立的10个成分的检测方法可行。
1.4 提取回收率及基质效应
10个检测成分在高、中、低浓度的提取回收率较高, 范围介于72.26%~110.85%, 且相对标准偏差均不高于10%, 说明10个成分在血中的提取回收率良好, 符合生物样品分析要求, 可用于定量检测。各成分基质效应计算结果显示, 除红景天苷和特女贞苷在高、中、低浓度的基质回收率较高且相对稳定外, 其余成分在不同浓度下的基质效应均较大且差异明显说明待测成分受血中成分干扰较大。
1.5 稳定性
高、中、低浓度的不同血浆样本中10个成分的稳定性(包括4 ℃、48 h内稳定性, 室温放置4 h稳定性, 冻融稳定性以及长期稳定性) 良好, 结果测得实际值均在理论值的89.13%~125.12%之间波动, RSD均低于11.35%。但是考虑到基质本身的易变特性, 生物样本应避免保存较长时间, 以防干扰实验结果。
2 药代动力学研究
以标准曲线法计算10个检测成分的血药浓度, 利用GraphPad Prism 7.00软件以平均血药浓度对时间作图, 得10个检测成分的平均血药浓度-时间曲线(图 2), 女贞子和酒女贞子水提物不同给药组中各成分的药代动力学参数及统计学差异性分析结果见表 3。
分析各成分的药代动力学参数和给药剂量可以发现, 羟基酪醇、酪醇及红景天苷3种苯乙醇类成分虽然在生药中含量较低, 但是其AUC0-24 h在10种成分中最高、Cmax最大(具有统计学意义), 且tmax较小, 推测3类成分释放吸收到体循环的速度较快和程度较好, 可能是女贞子和酒女贞子给药后的主要入血成分; 相反, 虽然环烯醚萜类成分为女贞子中的主要化学成分, 但与女贞子生药中的高含量相比, 女贞子和酒女贞子给药后环烯醚萜类成分的AUC0-24 h均较小, Cmax较低, 且tmax较大, 因此推测该类成分释放吸收到体循环的程度较差。
通过比较女贞子组和酒女贞子组的药代参数发现, 酒女贞子组中羟基酪醇、酪醇、红景天苷、毛蕊花糖苷、松果菊糖苷、橄榄苦苷、女贞苷G13及oleonuezhenide的tmax值均小于女贞子组, 说明相较于女贞子, 酒女贞子中的以上成分在进入人体后可以发挥速效的作用, 较快到达血药浓度峰值; 相反特女贞苷和齐墩果酸的tmax却延长, 进一步计算二者的相对生物利用度发现其数据较高, 特女贞苷为112.16%, 齐墩果酸为241.90%, 推测酒女贞子给药环境下进入人体中的两种成分可能产生缓释、长效的作用。
观察药-时曲线发现, 多种成分出现二次达峰现象, 但略有不同。酪醇和羟基酪醇在女贞子和酒女贞子给药组中均出现二次达峰, 但是红景天苷仅在酒女贞组出现二次达峰。
结合红景天苷和女贞子中其他成分的结构特征及前期研究中发现的体外生药中的化学成分转化机制(图 3) 推测, 女贞子或酒女贞子水提物进入体内后, 红景天苷成分作为入血成分继续参与体内代谢转化(浓度下降), 同时亦可能是其他类成分的代谢产物(浓度上升), 其血药浓度可能由其产生速率和代谢速率共同决定。推测可能在酒女贞子中, 由于酒制这一特殊处理导致药物进入体内后其他成分代谢产生红景天苷片段的速率提高, 进而导致该组出现双峰现象。而酪醇和羟基酪醇由于其片段小且多数成分代谢后均会产生该片段, 因此两组中均出现二次达峰。
通过分析特女贞苷、橄榄苦苷、女贞苷G13以及oleonuezhenide共计四种环烯醚萜类成分的药-时曲线发现, 4种成分中, 特女贞苷和橄榄苦苷、女贞苷G13和oleonuezhenide两组成分具有相似的药代动力学行为, 结合其化学结构发现, 推测可能与两组成分中各自的苷元相同只是连接糖的数目不同有关。
讨论
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为减少血样中蛋白质以及其他血中成分对检测成分的干扰, 同时保证对内标物的溶解性, 实验中比较了不同的蛋白沉淀试剂, 结果显示乙腈的效果最佳。在选择残渣复溶溶剂时, 为提高每类检测成分的溶解性, 本文考察了3种溶剂, 结果发现80%甲醇为最佳复溶溶剂。
在使用LC-QQQ-MS过程中, 首先应考察每个单体成分的最佳质谱条件, 实现质谱中各成分的完全电离和裂解。因此, 在正式实验前, 对每一个成分的质谱条件进行摸索, 确定每个成分的最佳离子模式、离子对、电离电压和碰撞能量。结合优化后的色谱条件, 建立女贞子中10个主要成分和京尼平苷内标物的专属检测条件, 保证生物样本在化学成分含量测定的准确性。
羟基酪醇、酪醇、红景天苷、毛蕊花糖苷、松果菊糖苷、橄榄苦苷、女贞苷G13及oleonuezhenide的tmax值在酒女贞子给药后更小, 说明: 在该给药环境下上述成分起效可能更快, 可以发挥速效的作用。此外, 特女贞苷和齐墩果酸的tmax延长, 相对生物利用度较高, 推测酒女贞子给药环境下两成分可能产生缓释、长效的作用。以上特征说明中医临床上主要采用酒女贞子入药的科学性。现代药理学研究中具有良好的提高免疫力作用的苯乙醇类成分(羟基酪醇、酪醇及红景天苷) 在女贞子和酒女贞子给药后AUC0-24 h均较高, 说明其吸收入血的程度较好, 这也提示苯乙醇类成分可能是女贞子样本发挥药效的直接物质基础。但是, 女贞子与酒女贞子给药后各成分tmax和AUC0-24 h存在显著差异的原因可能是多方面的, 一方面女贞子和酒女贞子样本中各成分的含量本身是不一致的, 另一方面可能由于黄酒等外界因素介入所致, 具体原因尚需进一步深入研究。
作者贡献: 纪鑫负责实验方案的设计、完成所有实验研究并撰写论文, 李春负责实验方案的设计和组织整个研究, 刘晓谦为实验方法的开发提供指导, 高陆提供女贞子样品并提供资金支持, 肖苏萍和梁曜华帮助校对论文, 王智民审阅论文并提供经费支持。
利益冲突: 本研究不存在任何利益冲突。
基金
收起
  • 国家中药标准化项目(ZYBZH-C-JL-26)
  • 国家科技重大专项_重大新药创制项目(2018ZX09721004-001)
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参考文献 引证文献
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2021年第56卷第12期
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doi: 10.16438/j.0513-4870.2021-0835
  • 接收时间：2021-06-05
  • 首发时间：2025-12-18
  • 出版时间：2021-12-12
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  • 收稿日期：2021-06-05
  • 修回日期：2021-09-24
基金
国家中药标准化项目(ZYBZH-C-JL-26)
国家科技重大专项_重大新药创制项目(2018ZX09721004-001)
作者信息
    1.中国中医科学院中药研究所, 中药质量控制技术国家工程实验室, 北京 100700
    2.修正药业集团股份有限公司, 吉林 长春 130012
    3.中国中药有限公司, 北京 102600

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*李春, Tel: 86-10-84014128, E-mail:
王智民, E-mail:
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https://castjournals.cast.org.cn/joweb/yxxb/CN/10.16438/j.0513-4870.2021-0835
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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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