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Article(id=1239238141656232600, tenantId=1146029695717560320, journalId=1205117023404326918, issueId=1239238136711139764, articleNumber=null, orderNo=null, doi=10.16155/j.0254-1793.2023-0302, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=null, receivedDateStr=null, revisedDate=1710691200000, revisedDateStr=2024-03-18, acceptedDate=null, acceptedDateStr=null, onlineDate=1773386996901, onlineDateStr=2026-03-13, pubDate=1722355200000, pubDateStr=2024-07-31, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1773386996901, onlineIssueDateStr=2026-03-13, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1773386996901, creator=13701087609, updateTime=1773386996901, updator=13701087609, issue=Issue{id=1239238136711139764, tenantId=1146029695717560320, journalId=1205117023404326918, year='2024', volume='44', issue='7', pageStart='1105', pageEnd='1284', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1773386995723, creator=13701087609, updateTime=1773387118529, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1239238651851370909, tenantId=1146029695717560320, journalId=1205117023404326918, issueId=1239238136711139764, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1239238651851370910, tenantId=1146029695717560320, journalId=1205117023404326918, issueId=1239238136711139764, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1202, endPage=1211, ext={EN=ArticleExt(id=1239238142578979513, articleId=1239238141656232600, tenantId=1146029695717560320, journalId=1205117023404326918, language=EN, title=Comparative pharmacokinetics of characteristic components of Scutellariae Radix in rats plasma after oral administration of Scutellariae Radix and Niuhuang Jiedu tablets, columnId=1239184757519602223, journalTitle=Chinese Journal of Pharmaceutical Analysis, columnName=Metabolism Analysis, runingTitle=null, highlight=null, articleAbstract=
Objective:

To establish an HPLC-MS/MS method for the simultaneous determination of six characteristic components of Scutellariae Radix including baicalein, baicalin, wogonin, wogonoside, chrysin and oroxylin A in rat plasma, and to compare their pharmacokinetic profiles after oral administration of Scutellariae Radix and Niuhuang Jiedu tablets (NHJDT) to rats.

Methods:

Rats were given 250 mg·kg-1 of NHJDT suspension or the prescribed equivalent amount of Scutellariae Radix aqueous extract, and plasma samples were collected at different time intervals. Naringenin was used as internal standard. After precipitated with methanol, the plasma samples were separated on an Inertsil C8-3 (150 mm×4.6 mm, 5 μm) column by linear gradient elution with 0.1% formic acid solution(A)-0.1% formic acid-methanol(B) as mobile phase. The flow rate was 1.0 mL·min-1, and the column temperature was 35 ℃. The analytes were detected by tandem mass spectrometry with the electrospray ionization (ESI) source combined with multiple reaction monitoring(MRM) mode in positive ion mode. The pharmacokinetic parameters were calculated and statistically analyzed.

Results:

The six characteristic components of Scutellariae Radix were all in good linear relationships in the range of 5-500 ng·mL-1. The RSDs for accuracy test were in the range of 88.43%-108.6%, and the RSDs for inter-batch and intra-batch precision tests were all below 15%. The matrix effect and plasma stability met the requirements of methodology validation in biological sample analysis. Baicalin and wogonoside were the major components detected in rat plasma after oral gavage of Scutellariae Radix aqueous extract and NHJDT suspension. The AUC0-t of wogonoside was significantly increased in NHJDT group compared with Scutellariae Radix group. Furthermore, the Cmax of wogonoside and baicalin were significantly increased while the Tmax was decreased after NHJDT suspension administration.

Conclusion:

This method is specific and sensitive for the determination of six characteristic components of Scutellariae Radix, and suitable for pharmacokinetic study of rat plasma. NHJDT with co-existing components enhances the absorption and influences the pharmacokinetic behaviors of active ingredients of Scutellariae Radix.

, correspAuthors=Tai-jun HANG, Xiao WU, 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=Yue-xin LIU, Min SONG, Tai-jun HANG, Xiao WU), CN=ArticleExt(id=1239238143669498630, articleId=1239238141656232600, tenantId=1146029695717560320, journalId=1205117023404326918, language=CN, title=牛黄解毒片及黄芩大鼠给药后血浆中黄芩特征成分药代动力学的比较研究*, columnId=1239184757708345914, journalTitle=药物分析杂志, columnName=代谢分析, runingTitle=null, highlight=null, articleAbstract=
目的：

建立高效液相色谱-串联质谱法（HPLC-MS/MS法）同时检测大鼠血浆中6个黄芩特征成分（黄芩素、黄芩苷、汉黄芩素、汉黄芩苷、白杨素及千层纸素A）的含量，比较大鼠牛黄解毒片及黄芩给药后黄芩特征成分在大鼠体内药代动力学行为的差异。

方法：

2组大鼠分别灌胃给予牛黄解毒片混悬液250 mg·kg-1或处方等量的黄芩饮片提取液，收集不同时间点血浆样本，以柚皮素为内标，经甲醇沉淀蛋白后，采用Inertsil C8-3（150 mm×4.6 mm，5 μm）色谱柱，以0.1%甲酸水溶液（A）-0.1%甲酸甲醇溶液（B）为流动相，线性梯度洗脱，流速1.0 mL·min-1，柱温35 ℃，采用电喷雾离子源（ESI），正离子扫描，多反应监测模式（MRM）检测黄芩特征成分，并计算药代动力学参数。

结果：

黄芩素、黄芩苷、汉黄芩素、汉黄芩苷、白杨素及千层纸素A 6个黄芩特征成分均在5~500 ng·mL-1范围内线性关系良好，准确度为88.43%~108.6%，批间精密度及批内精密度均<15%，基质效应和血浆样品稳定性均可满足生物样品分析要求。大鼠灌胃黄芩饮片提取液及牛黄解毒片混悬液后，血浆中检测出黄芩苷及汉黄芩苷2个主要成分；与单味黄芩组比较，牛黄解毒片组给药后大鼠血浆中汉黄芩苷的AUC0-t、黄芩苷与汉黄芩苷的Cmax均显著增加，Tmax显著缩短。

结论：

建立的方法能同时测定黄芩6个特征成分，且专属性强，灵敏度高，适用于大鼠血浆药代动力学研究。牛黄解毒片复方配伍增强了黄芩的特征成分在大鼠体内的吸收利用，改变了黄芩特征成分的药代动力学行为。

, correspAuthors=杭太俊, 吴骁, authorNote=null, correspAuthorsNote=
** 杭太俊　Tel：（025）83271090；E-mail：；
吴骁　Tel：（025）85811357；E-mail：
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Tel：13163006883；E-mail：

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China J Chin Mater Med， 2016， 41(18)： 3425, articleTitle=Mechanism of Rhei Radix et Rhizoma combined with Scutellariae Radix on liver inflammation in rats with endotoxin disease based on p38MAPK pathway, refAbstract=null)], funds=[Fund(id=1239238151575761000, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238141656232600, awardId=82104523, language=CN, fundingSource=* 国家自然科学基金资助项目(82104523), fundOrder=null, country=null), Fund(id=1239238151655452781, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238141656232600, awardId=BK20200843, language=CN, fundingSource=江苏省自然科学基金青年基金资助项目(BK20200843), fundOrder=null, country=null), Fund(id=1239238151735144565, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238141656232600, awardId=XPT82104523, language=CN, fundingSource=南京中医药大学国家自然科学基金青年科学基金配套经费项目(XPT82104523), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1239238143887602457, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238141656232600, xref=1., ext=[AuthorCompanyExt(id=1239238143891796762, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238141656232600, companyId=1239238143887602457, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1.TIPR Pharmaceutical Responsible Co., Ltd., Tianjin 300301, China), AuthorCompanyExt(id=1239238143895991068, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238141656232600, companyId=1239238143887602457, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1.天津药物研究院药业有限责任公司，天津 300301)]), AuthorCompany(id=1239238143992460064, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238141656232600, xref=2., ext=[AuthorCompanyExt(id=1239238144000848674, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238141656232600, companyId=1239238143992460064, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 210009, China), AuthorCompanyExt(id=1239238144005042979, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238141656232600, companyId=1239238143992460064, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.中国药科大学药物分析系，南京210009)]), AuthorCompany(id=1239238144067957545, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238141656232600, xref=3., ext=[AuthorCompanyExt(id=1239238144076346154, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238141656232600, companyId=1239238144067957545, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=3.Nanjing University of Chinese Medicine, Nanjing 210023, China), AuthorCompanyExt(id=1239238144084734762, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238141656232600, companyId=1239238144067957545, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=3.南京中医药大学，南京 210023)])], figs=[ArticleFig(id=1239238148606193668, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238141656232600, language=EN, label=Fig.1, caption=Multiple reaction monitoring chromatograms of characteristic components of Scutellariae Radix and internal standard, figureFileSmall=gzgT4jdIKeK9f3bzKB4POA==, figureFileBig=JoR1YrxbKh8bP3Li2n5yUw==, tableContent=null), ArticleFig(id=1239238148685885448, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238141656232600, language=CN, label=图1, caption=黄芩特征成分和内标多反应监测色谱图

1.白杨素(chrysin)　2.黄芩素(baicalein)　3.柚皮素(naringenin)　4.汉黄芩素(wogonin)、千层纸素A(oroxylin A)　5.黄芩苷(baicalin)　6.汉黄芩苷(wogonoside)

, figureFileSmall=gzgT4jdIKeK9f3bzKB4POA==, figureFileBig=JoR1YrxbKh8bP3Li2n5yUw==, tableContent=null), ArticleFig(id=1239238150330052629, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238141656232600, language=EN, label=Fig.2, caption=Mean plasma concentration-time profiles of baicalin (A) and wogonoside (B) in 10 rats after oral administration of Scutellariae Radix aqueous extract and NHJDT suspension，respectively, figureFileSmall=balVLWXGEA/SmhKgb0owrQ==, figureFileBig=WCBxjz7Hokk8wKlqzc+vdw==, tableContent=null), ArticleFig(id=1239238150418133017, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238141656232600, language=CN, label=图2, caption=10只大鼠灌胃黄芩饮片提取液及牛黄解毒片混悬液后黄芩苷(A)与汉黄芩苷(B)平均血药浓度-时间曲线, figureFileSmall=balVLWXGEA/SmhKgb0owrQ==, figureFileBig=WCBxjz7Hokk8wKlqzc+vdw==, tableContent=null), ArticleFig(id=1239238150497824801, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238141656232600, language=EN, label=Tab.1, caption=

MS parameters for characteristic components of Scutellariae Radix and internal standard

, figureFileSmall=null, figureFileBig=null, tableContent=
序号(No.)化合物(compound)母离子(precursor ion)m/z子离子(production)m/z碰撞能(CE)/eV
1白杨素(chrysin)255.0150.027
2黄芩素(baicalein)271.0123.029
3柚皮素(naringenin)273.0153.021
4汉黄芩素(wogonin)285.0270.021
5千层纸素A(oroxylin A)285.0270.021
6黄芩苷(baicalin)447.0271.019
7汉黄芩苷(wogonoside)461.0285.016
), ArticleFig(id=1239238150590099498, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238141656232600, language=CN, label=表1, caption=

黄芩特征成分及内标的质谱分析参数

, figureFileSmall=null, figureFileBig=null, tableContent=
序号(No.)化合物(compound)母离子(precursor ion)m/z子离子(production)m/z碰撞能(CE)/eV
1白杨素(chrysin)255.0150.027
2黄芩素(baicalein)271.0123.029
3柚皮素(naringenin)273.0153.021
4汉黄芩素(wogonin)285.0270.021
5千层纸素A(oroxylin A)285.0270.021
6黄芩苷(baicalin)447.0271.019
7汉黄芩苷(wogonoside)461.0285.016
), ArticleFig(id=1239238150678179889, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238141656232600, language=EN, label=Tab.2, caption=

Precision and accuracy of characteristic components of Scutellariae Radix

, figureFileSmall=null, figureFileBig=null, tableContent=
分析物
(analyte)		浓度
(concentration)/(ng·mL-1)		批间(inter-batch)(n=18)批内(intra-batch)(n=6)
实测值
(determined)±SD/(ng·mL-1)		准确度
(accuracy)
RE/%		精密度
(precision)
RSD/%		实测值
(determined)±SD/ (ng·mL-1)		准确度
(accuracy)
RE/%		精密度
(precision)
RSD/%
黄芩素(baicalein)15.0913.77±1.24591.259.013.94±0.726 992.975.2
150.9139.3±8.42592.326.0142.6±7.87295.065.5
402.4356.0±45.4988.4612.8377.4±9.34194.352.5
黄芩苷(baicalin)15.2114.87±1.07997.787.314.80±0.336 298.692.3
152.1142.9±4.35793.943.0144.3±6.31296.184.4
405.6358.7±38.6688.4310.8376.9±10.8994.222.9
汉黄芩素(wogonin)15.1216.17±1.363106.98.415.53±0.378 3103.62.4
151.2155.1±6.521102.64.2152.3±12.03101.67.9
403.2382.9±4.81594.971.3381.4±11.0095.342.9
汉黄芩苷(wogonoside)15.0915.47±1.508102.59.714.76±0.623 398.394.2
150.9150.4±16.2099.6910.8144.3±4.78296.233.3
402.4388.6±19.6396.565.1387.4±11.5896.863.0
白杨素(chrysin)15.0316.18±0.846 9107.75.215.93±0.327 3106.22.1
150.3160.3±13.44106.78.4159.6±7.853106.44.9
400.8386.6±13.6996.473.5382.0±12.9895.493.4
千层纸素A(oroxylin A)15.1216.43±0.778 6108.64.716.14±0.497 6107.63.1
151.2157.0±21.40103.813.6156.5±9.520104.36.1
403.2375.7±40.3293.1910.7374.5±14.7493.613.9
), ArticleFig(id=1239238150795620412, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238141656232600, language=CN, label=表2, caption=

黄芩特征成分的准确度与精密度

, figureFileSmall=null, figureFileBig=null, tableContent=
分析物
(analyte)		浓度
(concentration)/(ng·mL-1)		批间(inter-batch)(n=18)批内(intra-batch)(n=6)
实测值
(determined)±SD/(ng·mL-1)		准确度
(accuracy)
RE/%		精密度
(precision)
RSD/%		实测值
(determined)±SD/ (ng·mL-1)		准确度
(accuracy)
RE/%		精密度
(precision)
RSD/%
黄芩素(baicalein)15.0913.77±1.24591.259.013.94±0.726 992.975.2
150.9139.3±8.42592.326.0142.6±7.87295.065.5
402.4356.0±45.4988.4612.8377.4±9.34194.352.5
黄芩苷(baicalin)15.2114.87±1.07997.787.314.80±0.336 298.692.3
152.1142.9±4.35793.943.0144.3±6.31296.184.4
405.6358.7±38.6688.4310.8376.9±10.8994.222.9
汉黄芩素(wogonin)15.1216.17±1.363106.98.415.53±0.378 3103.62.4
151.2155.1±6.521102.64.2152.3±12.03101.67.9
403.2382.9±4.81594.971.3381.4±11.0095.342.9
汉黄芩苷(wogonoside)15.0915.47±1.508102.59.714.76±0.623 398.394.2
150.9150.4±16.2099.6910.8144.3±4.78296.233.3
402.4388.6±19.6396.565.1387.4±11.5896.863.0
白杨素(chrysin)15.0316.18±0.846 9107.75.215.93±0.327 3106.22.1
150.3160.3±13.44106.78.4159.6±7.853106.44.9
400.8386.6±13.6996.473.5382.0±12.9895.493.4
千层纸素A(oroxylin A)15.1216.43±0.778 6108.64.716.14±0.497 6107.63.1
151.2157.0±21.40103.813.6156.5±9.520104.36.1
403.2375.7±40.3293.1910.7374.5±14.7493.613.9
), ArticleFig(id=1239238150879506498, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238141656232600, language=EN, label=Tab.3, caption=

Matrix effect and extraction recovery of characteristic components of Scutellariae Radix

, figureFileSmall=null, figureFileBig=null, tableContent=
分析物
(analyte)		浓度
(concentration)/(ng·mL-1)		基质效应
(matrix effect)±SD/%		RSD/%提取回收率
(extraction recovery)±SD/%		RSD/%
黄芩素(baicalein)15.09104.5±10.129.744.43±1.6993.8
150.991.84±4.8735.347.20±3.7778.0
402.486.09±2.3172.761.79±7.13611.6
黄芩苷(baicalin)15.2186.69±5.5126.489.09±7.1518.0
152.1100.0±3.2623.377.25±1.9852.6
405.692.88±3.4443.799.36±10.8310.9
汉黄芩素(wogonin)15.12124.2±5.6614.679.39±2.4623.1
151.2127.2±6.7995.378.27±3.1924.1
403.2108.9±3.2363.094.19±10.5511.2
汉黄芩苷(wogonoside)15.09101.8±5.2165.151.49±3.3386.5
150.9105.9±6.6216.349.84±2.6195.3
402.499.96±3.1723.266.42±7.65211.5
白杨素(chrysin)15.03126.6±14.2911.373.21±2.5703.5
150.3117.3±9.9218.576.91±4.3145.6
400.897.35±4.2384.489.27±10.7712.1
千层纸素A(oroxylin A)15.12117.8±5.2264.479.05±5.4096.8
151.2122.2±10.908.979.42±2.7923.5
403.2101.8±3.6383.696.42±12.7413.2
), ArticleFig(id=1239238150984364105, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238141656232600, language=CN, label=表3, caption=

黄芩特征成分的基质效应与提取回收率(n=6)

, figureFileSmall=null, figureFileBig=null, tableContent=
分析物
(analyte)		浓度
(concentration)/(ng·mL-1)		基质效应
(matrix effect)±SD/%		RSD/%提取回收率
(extraction recovery)±SD/%		RSD/%
黄芩素(baicalein)15.09104.5±10.129.744.43±1.6993.8
150.991.84±4.8735.347.20±3.7778.0
402.486.09±2.3172.761.79±7.13611.6
黄芩苷(baicalin)15.2186.69±5.5126.489.09±7.1518.0
152.1100.0±3.2623.377.25±1.9852.6
405.692.88±3.4443.799.36±10.8310.9
汉黄芩素(wogonin)15.12124.2±5.6614.679.39±2.4623.1
151.2127.2±6.7995.378.27±3.1924.1
403.2108.9±3.2363.094.19±10.5511.2
汉黄芩苷(wogonoside)15.09101.8±5.2165.151.49±3.3386.5
150.9105.9±6.6216.349.84±2.6195.3
402.499.96±3.1723.266.42±7.65211.5
白杨素(chrysin)15.03126.6±14.2911.373.21±2.5703.5
150.3117.3±9.9218.576.91±4.3145.6
400.897.35±4.2384.489.27±10.7712.1
千层纸素A(oroxylin A)15.12117.8±5.2264.479.05±5.4096.8
151.2122.2±10.908.979.42±2.7923.5
403.2101.8±3.6383.696.42±12.7413.2
), ArticleFig(id=1239238151085027405, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238141656232600, language=EN, label=Tab. 4, caption=

Stability of characteristic components of Scutellariae Radix under different conditions

, figureFileSmall=null, figureFileBig=null, tableContent=
分析物
(analyte)		浓度
(concentration)/(ng·mL-1)		实测值(determined)/(ng·mL-1)
进样器
(autosampler) 15 ℃		冻融3次
(three freeze-thaw cycles)		室温
(room-temperature) 25 ℃
黄芩素(baicalein)15.0915.66±1.42616.59±3.34914.16±1.687
402.4381.3±11.66385.9±23.35382.0±29.82
黄芩苷(baicalin)15.2115.25±4.18217.90±3.27915.63±2.032
405.6354.4±14.61404.1±24.19375.8±21.98
汉黄芩素(wogonin)15.1215.01±0.561916.88±1.79815.26±1.500
403.2370.2±17.23362.8±17.71368.9±16.40
汉黄芩苷(wogonoside)15.0914.51±1.32414.90±1.30712.88±1.637
402.4359.3±13.79387.2±23.55369.8±16.13
白杨素(chrysin)15.0312.76±0.640 515.60±1.15614.73±1.057
400.8380.7±13.70328.2±9.806337.1±7.657
千层纸素A(oroxylin A)15.1212.57±0.660 716.11±1.53315.13±0.9541
403.2380.2±14.50340.9±7.871343.6±8.498
), ArticleFig(id=1239238151206662228, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238141656232600, language=CN, label=表4, caption=

黄芩特征成分在不同条件下的稳定性(n=3)

, figureFileSmall=null, figureFileBig=null, tableContent=
分析物
(analyte)		浓度
(concentration)/(ng·mL-1)		实测值(determined)/(ng·mL-1)
进样器
(autosampler) 15 ℃		冻融3次
(three freeze-thaw cycles)		室温
(room-temperature) 25 ℃
黄芩素(baicalein)15.0915.66±1.42616.59±3.34914.16±1.687
402.4381.3±11.66385.9±23.35382.0±29.82
黄芩苷(baicalin)15.2115.25±4.18217.90±3.27915.63±2.032
405.6354.4±14.61404.1±24.19375.8±21.98
汉黄芩素(wogonin)15.1215.01±0.561916.88±1.79815.26±1.500
403.2370.2±17.23362.8±17.71368.9±16.40
汉黄芩苷(wogonoside)15.0914.51±1.32414.90±1.30712.88±1.637
402.4359.3±13.79387.2±23.55369.8±16.13
白杨素(chrysin)15.0312.76±0.640 515.60±1.15614.73±1.057
400.8380.7±13.70328.2±9.806337.1±7.657
千层纸素A(oroxylin A)15.1212.57±0.660 716.11±1.53315.13±0.9541
403.2380.2±14.50340.9±7.871343.6±8.498
), ArticleFig(id=1239238151349268572, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238141656232600, language=EN, label=Tab.5, caption=

Pharmacokinetic parameters of baicalin and wogonoside in rats after oral administration of Scutellariae Radix aqueous extract and NHJDT suspension，respectively

, figureFileSmall=null, figureFileBig=null, tableContent=
参数
（parameter）		黄芩苷（baicalin）汉黄芩苷（wogonoside）
黄芩饮片提取液
（Scutellariae Radix aqueous extract）		牛黄解毒片混悬液
（NHJDT suspension）		黄芩饮片提取液
（Scutellariae Radix aqueous extract）		牛黄解毒片混悬液
（NHJDT suspension）
Cmax/(μg·L-1)93.51±17.53*225.2±31.09*56.62±10.04*120.0±24.37*
Tmax/h7.317±1.610*0.171 8±0.039 22*8.850±1.269*2.505±1.339*
T1/2/h11.62±3.0475.795±0.851 417.81±6.3638.105±2.203
AUC0-t/(μg·h·L-1)785.5±112.71 223±249.4529.1±95.96*932.5±141.4*
AUC0-∞/(μg·h·L-1)1 082±135.61 429±288.5943.5±150.6995.3±83.61
MRT/h8.239±0.472 57.341±0.319 57.951±0.427 27.632±0.317 9
), ArticleFig(id=1239238151454126174, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239238141656232600, language=CN, label=表5, caption=

大鼠灌胃黄芩饮片提取液及牛黄解毒片混悬液后黄芩苷与汉黄芩苷药代动力学参数(n=10)

, figureFileSmall=null, figureFileBig=null, tableContent=
参数
（parameter）		黄芩苷（baicalin）汉黄芩苷（wogonoside）
黄芩饮片提取液
（Scutellariae Radix aqueous extract）		牛黄解毒片混悬液
（NHJDT suspension）		黄芩饮片提取液
（Scutellariae Radix aqueous extract）		牛黄解毒片混悬液
（NHJDT suspension）
Cmax/(μg·L-1)93.51±17.53*225.2±31.09*56.62±10.04*120.0±24.37*
Tmax/h7.317±1.610*0.171 8±0.039 22*8.850±1.269*2.505±1.339*
T1/2/h11.62±3.0475.795±0.851 417.81±6.3638.105±2.203
AUC0-t/(μg·h·L-1)785.5±112.71 223±249.4529.1±95.96*932.5±141.4*
AUC0-∞/(μg·h·L-1)1 082±135.61 429±288.5943.5±150.6995.3±83.61
MRT/h8.239±0.472 57.341±0.319 57.951±0.427 27.632±0.317 9
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牛黄解毒片及黄芩大鼠给药后血浆中黄芩特征成分药代动力学的比较研究*
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刘玥昕 1, 2 , 宋敏 2 , 杭太俊 2, ** , 吴骁 3, **
药物分析杂志 | 代谢分析 2024,44(7): 1202-1211
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药物分析杂志 | 代谢分析 2024, 44(7): 1202-1211
牛黄解毒片及黄芩大鼠给药后血浆中黄芩特征成分药代动力学的比较研究*
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刘玥昕1, 2 , 宋敏2, 杭太俊2, ** , 吴骁3, **
作者信息
  • 1.天津药物研究院药业有限责任公司，天津 300301
  • 2.中国药科大学药物分析系，南京210009
  • 3.南京中医药大学，南京 210023

    • Tel：13163006883；E-mail：

通讯作者:

** 杭太俊　Tel：（025）83271090；E-mail：；
吴骁　Tel：（025）85811357；E-mail：
Comparative pharmacokinetics of characteristic components of Scutellariae Radix in rats plasma after oral administration of Scutellariae Radix and Niuhuang Jiedu tablets
Yue-xin LIU1, 2 , Min SONG2, Tai-jun HANG2, ** , Xiao WU3, **
Affiliations
  • 1.TIPR Pharmaceutical Responsible Co., Ltd., Tianjin 300301, China
  • 2.Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 210009, China
  • 3.Nanjing University of Chinese Medicine, Nanjing 210023, China
出版时间: 2024-07-31 doi: 10.16155/j.0254-1793.2023-0302
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摘要
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目的：

建立高效液相色谱-串联质谱法（HPLC-MS/MS法）同时检测大鼠血浆中6个黄芩特征成分（黄芩素、黄芩苷、汉黄芩素、汉黄芩苷、白杨素及千层纸素A）的含量，比较大鼠牛黄解毒片及黄芩给药后黄芩特征成分在大鼠体内药代动力学行为的差异。

方法：

2组大鼠分别灌胃给予牛黄解毒片混悬液250 mg·kg-1或处方等量的黄芩饮片提取液，收集不同时间点血浆样本，以柚皮素为内标，经甲醇沉淀蛋白后，采用Inertsil C8-3（150 mm×4.6 mm，5 μm）色谱柱，以0.1%甲酸水溶液（A）-0.1%甲酸甲醇溶液（B）为流动相，线性梯度洗脱，流速1.0 mL·min-1，柱温35 ℃，采用电喷雾离子源（ESI），正离子扫描，多反应监测模式（MRM）检测黄芩特征成分，并计算药代动力学参数。

结果：

黄芩素、黄芩苷、汉黄芩素、汉黄芩苷、白杨素及千层纸素A 6个黄芩特征成分均在5~500 ng·mL-1范围内线性关系良好，准确度为88.43%~108.6%，批间精密度及批内精密度均<15%，基质效应和血浆样品稳定性均可满足生物样品分析要求。大鼠灌胃黄芩饮片提取液及牛黄解毒片混悬液后，血浆中检测出黄芩苷及汉黄芩苷2个主要成分；与单味黄芩组比较，牛黄解毒片组给药后大鼠血浆中汉黄芩苷的AUC0-t、黄芩苷与汉黄芩苷的Cmax均显著增加，Tmax显著缩短。

结论：

建立的方法能同时测定黄芩6个特征成分，且专属性强，灵敏度高，适用于大鼠血浆药代动力学研究。牛黄解毒片复方配伍增强了黄芩的特征成分在大鼠体内的吸收利用，改变了黄芩特征成分的药代动力学行为。

黄芩  /  牛黄解毒片  /  黄芩苷  /  汉黄芩苷  /  高效液相色谱-串联质谱法  /  比较药代动力学  /  大鼠血浆
Objective:

To establish an HPLC-MS/MS method for the simultaneous determination of six characteristic components of Scutellariae Radix including baicalein, baicalin, wogonin, wogonoside, chrysin and oroxylin A in rat plasma, and to compare their pharmacokinetic profiles after oral administration of Scutellariae Radix and Niuhuang Jiedu tablets (NHJDT) to rats.

Methods:

Rats were given 250 mg·kg-1 of NHJDT suspension or the prescribed equivalent amount of Scutellariae Radix aqueous extract, and plasma samples were collected at different time intervals. Naringenin was used as internal standard. After precipitated with methanol, the plasma samples were separated on an Inertsil C8-3 (150 mm×4.6 mm, 5 μm) column by linear gradient elution with 0.1% formic acid solution(A)-0.1% formic acid-methanol(B) as mobile phase. The flow rate was 1.0 mL·min-1, and the column temperature was 35 ℃. The analytes were detected by tandem mass spectrometry with the electrospray ionization (ESI) source combined with multiple reaction monitoring(MRM) mode in positive ion mode. The pharmacokinetic parameters were calculated and statistically analyzed.

Results:

The six characteristic components of Scutellariae Radix were all in good linear relationships in the range of 5-500 ng·mL-1. The RSDs for accuracy test were in the range of 88.43%-108.6%, and the RSDs for inter-batch and intra-batch precision tests were all below 15%. The matrix effect and plasma stability met the requirements of methodology validation in biological sample analysis. Baicalin and wogonoside were the major components detected in rat plasma after oral gavage of Scutellariae Radix aqueous extract and NHJDT suspension. The AUC0-t of wogonoside was significantly increased in NHJDT group compared with Scutellariae Radix group. Furthermore, the Cmax of wogonoside and baicalin were significantly increased while the Tmax was decreased after NHJDT suspension administration.

Conclusion:

This method is specific and sensitive for the determination of six characteristic components of Scutellariae Radix, and suitable for pharmacokinetic study of rat plasma. NHJDT with co-existing components enhances the absorption and influences the pharmacokinetic behaviors of active ingredients of Scutellariae Radix.

Scutellariae Radix  /  Niuhuang Jiedu tablets  /  baicalin  /  wogonoside  /  HPLC-MS/MS  /  comparative pharmacokinetics  /  rat plasma
刘玥昕, 宋敏, 杭太俊, 吴骁. 牛黄解毒片及黄芩大鼠给药后血浆中黄芩特征成分药代动力学的比较研究*. 药物分析杂志, 2024 , 44 (7) : 1202 -1211 . DOI: 10.16155/j.0254-1793.2023-0302
Yue-xin LIU, Min SONG, Tai-jun HANG, Xiao WU. Comparative pharmacokinetics of characteristic components of Scutellariae Radix in rats plasma after oral administration of Scutellariae Radix and Niuhuang Jiedu tablets[J]. Chinese Journal of Pharmaceutical Analysis, 2024 , 44 (7) : 1202 -1211 . DOI: 10.16155/j.0254-1793.2023-0302
正文
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牛黄解毒片作为清热解毒的经典名方，已有800年的应用历史[1]，具有抗菌消炎作用，临床疗效确切，用于治疗实火上攻所致的咽喉肿痛及牙龈肿痛等症状。其处方以人工牛黄、雄黄、石膏、大黄、黄芩、桔梗、冰片、甘草8味中药组成[2-3]。黄芩作为临床常见的清热解毒的中草药，是牛黄解毒片处方中的主要药味，是治疗呼吸道感染、肺湿热毒素滞留的要药，常与多种药物配伍使用，在新型冠状病毒肺炎的治疗中发挥了关键作用[4]。黄芩的特征成分为黄芩素、黄芩苷、汉黄芩素、汉黄芩苷、白杨素及千层纸素A等[5]。关于牛黄解毒片的配伍机理研究多从降低雄黄中砷的毒性方面展开[6]，尚没有黄芩配伍后特征成分体内代谢差异的报道[7]。而中药复方中各活性成分的药代动力学相互作用引发的药效行为是中药复方整体药效的本质。
本研究建立测定黄芩特征成分的HPLC-MS/MS方法，并应用该方法研究牛黄解毒片中黄芩主要成分在大鼠血浆中的经时过程，分析药代动力学特征，并与给药单味黄芩进行比较，从药代动力学角度揭示方剂配伍中与黄芩相关的特性。
1　仪器与材料
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1.1　仪器
Thermo ScientificTM UltiMateTM 3000高效液相色谱仪、TSQ Quantum Ultra AM型MS/MS联用仪(Thermo Finnigan公司)；XW-80C型旋涡混合器(上海青浦沪西仪器厂)；Explorer超纯水机(上海沉黄科学仪器有限公司)；BS21S型十万分之一天平(Sartorius公司)；BS110S型万分之一天平(Sartorius公司)；TGL-16台式高速冷冻离心机(湖南湘仪仪器有限公司)；高速多功能粉碎机(永康市天祺盛世工贸有限公司)；FD-1A-50型真空冷冻干燥机（北京博医康实验仪器有限公司）；KQ5200DB型数控超声波清洗器(中国昆山市超声仪器有限公司)。
1.2　药品与试剂
牛黄解毒片(北京同仁堂科技发展股份有限公司制药厂，批号15122090)，黄芩饮片(江苏省中医院)。对照品黄芩素(纯度98.85%，批号DST161212-024)、汉黄芩苷(纯度98.14%，批号DST170222-026)、千层纸素A(纯度98.75%，批号DST170315-041)、柚皮素(纯度98.76%，批号DST160928-100)均购自成都德思特生物技术有限公司；汉黄芩素(纯度93.3%，批号111514-201605)、黄芩苷(纯度93.3%，批号110715-201318)、白杨素(纯度93.3%，批号111701-200501)均购自中国食品药品检定研究院。
L-抗坏血酸(纯度99.7%，国药集团化学试剂有限公司)，甲醇(色谱纯、Tedia公司)，二甲亚砜(色谱纯，上海阿拉丁试剂有限公司)，甲酸铵(分析纯，南京化学试剂有限公司)，羧甲基纤维素钠（化学纯，南京化学试剂有限公司），肝素钠（Biosharp生物科技有限公司），氯化钠注射液（安徽双鹤药业有限责任公司），超纯水(18.25 MΩ·cm，自制)。
1.3　动物
SPF级SD大鼠20只，雌雄各半，体质量(200±20) g，上海杰思捷实验动物有限公司提供，实验动物生产许可证号为SCXK (沪)2013-0006。动物饲养于中国药科大学药学实验动物中心，饲养温度为(23±3) ℃，湿度为40%~70%，12 h照明。实验前禁食过夜12 h，自由饮水。所有动物实验符合实验室动物饲料和使用指导原则，并通过中国药科大学动物试验伦理委员会的同意。
2　方法与结果
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2.1　牛黄解毒片与黄芩的灌胃溶液制备
2.1.1　供试品定量分析
取牛黄解毒片适量，研磨成细粉，精密称取细粉1 g，置于50 mL烧杯中，加入甲醇25 mL，超声(40 kHz，200 W) 30 min，滤过，取续滤液待测。另取黄芩饮片10 g于烧杯中，加入超纯水200 mL，煎煮1 h，过滤，滤渣加入超纯水100 mL，继续煎煮1 h，过滤，合并2次所得滤液，-50 ℃冷冻干燥24 h，得黄芩冻干粉。精密称取黄芩冻干粉10 mg，置于100 mL量瓶中，加入甲醇约80 mL使溶解后，加甲醇稀释至刻度，摇匀，滤过，精密量取续滤液1 mL，置100 mL量瓶中，加甲醇稀释至刻度，摇匀，待测。运用HPLC法测定牛黄解毒片和黄芩冻干粉中各黄芩特征成分的含量。采用Inertsustain-C18(250 mm×4.6 mm，5 μm)色谱柱，以0.1%甲酸-水为流动相A，乙腈为流动相B，进行梯度洗脱(0~16 min，30%B；16~18 min，30%B→40%B；18~30 min，40%B；30~32 min，40%B→30%B；32~35 min，30%B)，流速1.0 mL·min-1，检测波长275 nm，柱温35 ℃，进样量20 μL，采用外标法计算含量。
经测定，牛黄解毒片中黄芩素含量为1.35 μg·mg-1，黄芩苷含量为11.5 μg·mg-1，汉黄芩素含量为0.612 μg·mg-1，汉黄芩苷含量为2.52 μg·mg-1，千层纸素A含量为0.232 μg·mg-1。黄芩冻干粉中黄芩素含量为1.86 μg·mg-1，黄芩苷含量为201 μg·mg-1，汉黄芩素含量为4.07 μg·mg-1，汉黄芩苷含量为44.2 μg·mg-1，千层纸素A含量为1.12 μg·mg-1。
2.1.2　灌胃溶液的制备
取牛黄解毒片7片，研磨成细粉，加0.5% CMC-Na溶液35 mL，充分混匀制成混悬液，作为灌胃溶液。按人用临床等效日剂量换算，大鼠给药剂量为250 mg·kg-1。实际给药剂量为黄芩素0.338 mg·kg-1、黄芩苷2.88 mg·kg-1、汉黄芩素0.153 mg·kg-1、汉黄芩苷0.63 mg·kg-1、千层纸素A 0.058 mg·kg-1。
取黄芩冻干粉61 mg，精密称定，加入生理盐水20 mL，充分溶解制成黄芩饮片提取液，作为灌胃溶液。根据供试品定量分析结果，按黄芩苷、汉黄芩苷与牛黄解毒片给药剂量相当换算。实际给药剂量为黄芩素0.026 mg·kg-1、黄芩苷2.87 mg·kg-1、汉黄芩素0.058 mg·kg-1、汉黄芩苷0.63 mg·kg-1、千层纸素A 0.016 mg·kg-1。
2.2　动物实验
SPF级SD大鼠20只，随机分为2组，每组10只，雌雄各半，分别灌胃黄芩饮片提取液及牛黄解毒片混悬液，于给药前0 h及给药后0.05、0.083、0.167、0.5、1、2、4、8、12、16、20、22、24 h大鼠眼内眦静脉丛取血0.2 mL至肝素化离心管中，4 000 r·min-1离心10 min，分取血浆置-20 ℃冰箱中保存待测。
2.3　溶液的配制
2.3.1　对照品储备液
精密称定黄芩素、黄芩苷、汉黄芩素、汉黄芩苷、白杨素及千层纸素A的对照品各约10 mg，分别置100 mL量瓶中，加甲醇约80 mL溶解后，加入20% L-抗坏血酸溶液5 mL，用甲醇稀释至刻度，配制成含1% L-抗坏血酸的0.1 mg·mL-1对照品储备液。
2.3.2　内标工作液
精密称取内标柚皮素约10 mg，置100 mL量瓶中，加甲醇约80 mL溶解后，加入20% L-抗坏血酸溶液5 mL，用甲醇稀释至刻度，制成含1% L-抗坏血酸的0.1 mg·mL-1的内标储备液。精密量取内标储备液1 mL，用甲醇稀释至1 μg·mL-1，即得内标工作液。
2.3.3　混合质控溶液
精密量取黄芩素、黄芩苷、汉黄芩素、汉黄芩苷、白杨素及千层纸素A的对照品储备液适量，用甲醇稀释成各化合物质量浓度均分别为45、450、1 200 ng·mL-1的混合质控溶液。
2.4　色谱-质谱条件
2.4.1　色谱条件
采用Inertsil C8-3(150 mm×4.6 mm，5 μm)色谱柱，以0.1%甲酸水溶液(A)-0.1%甲酸甲醇溶液(B)为流动相，线性梯度洗脱(0~1.0 min，35%B；1.0~1.5 min，35%B→75%B；1.5~7.0 min，75%B；7.0~7.1 min，75%B→35%B；7.1~8.0 min，35%B)，流速1.0 mL·min-1，柱温35 ℃，进样量30 μL。
2.4.2　质谱条件
采用电喷雾离子源，正离子检测模式(ESI+)，喷雾电压5 000 V，毛细管温度350 ℃，鞘气(N2)压力40 kPa，辅助气(N2)压力10 kPa，碰撞气(Ar)1.20 Pa。多级反应监测模式(MRM)，6个黄芩特征成分及内标柚皮素的质谱参数见表1。
2.5　血浆样品前处理
精密量取血浆样品0.1 mL于2 mL聚塑离心管中，精密加入20% L-抗坏血酸溶液40 μL、甲醇50 μL及内标工作液50 μL，涡旋混匀30 s，精密加入甲醇0.3 mL，涡旋混匀3 min，12 000 r·min-1离心10 min，取上清液37 ℃下氮吹至干，残渣加入初始比例流动相[0.1%甲酸水溶液-0.1%甲酸甲醇溶液(65∶35)]120 μL，涡旋混匀3 min，12 000 r·min-1离心10 min，取上清30 μL待进行分析。
2.6　方法学验证
2.6.1　专属性
取大鼠空白血浆0.1 mL，除用甲醇代替内标工作液外，其余照“2.5”项下方法操作，制得空白血浆样品溶液。精密量取黄芩素、黄芩苷、汉黄芩素、汉黄芩苷、白杨素及千层纸素A的对照品储备液适量，用甲醇稀释成1 500 ng·mL-1的混合对照品溶液；精密量取空白血浆0.1 mL，置2 mL离心管中，加入20% L-抗坏血酸溶液40 μL，精密加入混合对照品溶液50 μL，照“2.5”项下自“加入内标工作液50 μL”起操作，配制成标准血浆样品溶液。取大鼠灌胃30 min后的血浆样品，按“2.5”项下方法制备大鼠给药后血浆样品溶液。以上溶液按“2.4”项下条件进样测定，结果见图1。白杨素、黄芩素、柚皮素、汉黄芩素、千层纸素A、黄芩苷、汉黄芩苷的保留时间分别约为6.2、4.9、4.1、5.8、6.2、4.7、5.0 min。血浆内源性物质对测定无干扰。
2.6.2　线性关系及定量限
精密量取黄芩素、黄芩苷、汉黄芩素、汉黄芩苷、白杨素及千层纸素A的对照品储备液适量，用甲醇稀释成15、30、60、150、300、600、900、1 200，1 500 ng·mL-1系列混合对照品溶液。精密量取空白血浆0.1 mL，置2 mL离心管中，加入20% L-抗坏血酸溶液40 μL，分别精密加入各浓度混合对照品溶液50 μL，配制成黄芩素、黄芩苷、汉黄芩素、汉黄芩苷、白杨素及千层纸素A质量浓度分别为5、10、20、50、100、200、300、400、500 ng·mL-1的标准血浆样品，照“2.5”项下自“加入内标工作液50 μL”起操作，再按“2.4”项下条件进样测定，记录色谱图。以各成分峰面积(As)和内标峰面积(Ar)的比值Y对质量浓度(C，ng·mL-1)进行权重回归(1/C2)。得黄芩素、黄芩苷、汉黄芩素、汉黄芩苷、白杨素及千层纸素A的回归方程分别为
结果表明，各成分线性良好，相关系数r≥0.99；定量限均为5 ng·mL-1，不同浓度水平下各成分精密度良好(RSD<15%，n=6)，满足定量限分析测定的要求。
2.6.3　准确度与精密度
精密量取空白血浆0.1 mL，置2 mL离心管中，加入20% L-抗坏血酸溶液40 μL，分别精密加入混合质控溶液50 μL，制成15、150、400 ng·mL-1的质控血浆样品各6份，照“2.5”项下自“加入内标工作液50 μL”起操作得质控样品溶液，1个分析批内测定6次，计算批内变异。不同分析批测定3次，计算批间变异。结果如表2所示，各成分准确度在88.43%~108.6%，精密度RSD(n=6)<14%。准确度与精密度均符合生物样品的测定要求。
2.6.4　基质效应和提取回收率
精密量取甲醇0.1 mL，置2 mL离心管中，加入20% L-抗坏血酸溶液40 μL，分别精密加入混合质控溶液50 μL，照“2.5”项下自“加入内标工作液50 μL”起操作，即得基质效应对照溶液，进样测定，记录待测成分峰面积(As)和内标峰面积(Ar)的比值为A。取空白血浆0.1 mL，置2 mL离心管中，加入甲醇0.3 mL，涡旋混匀3 min，12 000 r·min-1离心10 min，取上清液加入20% L-抗坏血酸溶液40 μL，分别精密加入混合质控溶液50 μL及内标工作液50 μL，涡旋混匀30 s，照“2.5”项下自“37 ℃下氮吹至干”起同法操作，即得基质效应样品溶液，进样测定，记录待测成分峰面积(As)和内标峰面积(Ar)的比值为B。按B/A×100%计算基质效应因子。
照“2.6.3”项下方法分别配制质量浓度为15、150、400 ng·mL-1的质控血浆样品，照“2.5”项下自“加入内标工作液50 μL”起操作，即得提取回收率样品溶液，进样测定峰面积，根据与基质效应样品溶液峰面积的比值计算提取回收率。基质效应和提取回收率结果见表3，在低、中、高不同浓度水平下，质控样品的基质效应和提取回收率稳定，符合生物样本定量分析的要求。
2.6.5　稳定性
取“2.3.3”项下配制的45、1 200 ng·mL-1混合质控溶液50 μL，加入空白血浆0.1 mL，配成高、低2种浓度的质控血浆样品各3份。分别进行在室温(25 ℃)放置8 h稳定性、-20 ℃冷冻至少24 h-室温解冻循环3次稳定性、质控血浆样品处理后在进样器(15 ℃)放置24 h的稳定性进行考察，结果见表4。黄芩素、黄芩苷、汉黄芩素、汉黄芩苷、白杨素和千层纸素A浓度均无明显变化，稳定性良好。
2.7　药代动力学试验
取-20 ℃冰箱中保存的血浆样品，室温下融化，按“2.5”项下方法处理并测定。血浆中仅检测到黄芩苷及汉黄芩苷2个成分，其平均血药浓度-时间曲线见图2。所得数据经WinNonlin 7.0软件计算药代动力学参数，SPSS独立样本t检验分析，结果见表5。
3　讨论
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3.1　检测方法的开发
目前，黄芩的体内代谢分析主要为黄芩素、黄芩苷等单一成分的测定，无法实现黄芩多种特征成分的同时测定。本文采用HPLC-MS/MS法同时测定大鼠血浆中黄芩的6个特征成分，为更完整地评估黄芩药代动力学行为提供了有效途径。本研究对大鼠血浆样本前处理方法及色谱条件进行了优化，比较了甲醇沉淀、乙腈沉淀、二氯甲烷-四甲基叔丁基醚(1∶2)的液-液萃取法3种前处理方法，结果显示血浆样本经甲醇沉淀提取效率高，重现性好。处理过程中加入20% L-抗坏血酸溶液，防止黄酮类成分在前处理操作中被氧化[8]。另外，对色谱条件进行了优化，考察了使用甲醇或乙腈作为有机相、流动相中加入甲酸或甲酸铵及色谱柱种类对黄芩各特征成分保留时间、峰形及响应的影响，以增强分离效果、缩短分析时间及提高灵敏度。最终确定了以0.1%甲酸水溶液-0.1%甲酸甲醇溶液为流动相，Inertsil C8-3色谱柱(150 mm× 4.6 mm，5 μm)为最佳色谱条件。由于黄芩素及汉黄芩苷在血浆中的稳定性较差，导致二者回收率偏低，研究结果与文献报道[9-11]相符。
3.2　采样点的设计
在预实验中，黄芩苷及汉黄芩苷均在10 min内出现首个吸收峰，并在24 h时，血药浓度均已远低于达峰浓度的1/10，参考相关黄酮类药代动力学现有文献的采样时间[12-13]，本研究拟在10 min内设计较密集的采样点，采样终点设置为24 h，最终选用了给药前0 h及给药后0.05、0.083、0.167、0.5、1、2、4、8、12、16、20、22、24 h的采样点。
3.3　药动学特征讨论
研究结果表明，大鼠灌胃黄芩饮片提取液或牛黄解毒片混悬液后，血浆中仅检测出黄芩苷及汉黄芩苷2个成分，其他成分由于血浆浓度较低均未检出。牛黄解毒片及黄芩饮片含量测定结果表明，黄芩中主要成分为黄芩素、黄芩苷、汉黄芩素及汉黄芩苷，其他黄酮类成分均含量较低或未检出。另有文献报道表明，黄芩素及汉黄芩素在体循环中主要以Ⅱ相代谢产物的形式存在，即通过黄酮羟基上的取代反应，生成葡糖醛酸苷、硫酸酯及其他Ⅱ相代谢产物，其中黄芩苷及汉黄芩苷含量最高[14-16]。
中药复方成分复杂，各成分之间存在显著的相互作用，不仅表现为药效动力学的差异，也体现在药代动力学行为的变化。文献报道，很多中药代谢吸收的药代动力学曲线不是经典的房室模型，不具有线性药代动力学特征，在缓慢吸收的同时也伴随代谢和排泄的过程，造成吸收相和代谢相的药时曲线相对平缓[6,17-18]。本研究结果表明，黄芩苷及汉黄芩苷在大鼠体内呈明显双峰现象，是非线性药代动力学特征，与文献报道[19-20]一致，基于此，为保证实验结果的准确性，药代动力学结果在以Cmax和Tmax判定的基础上，通过AUC进一步分析佐证。
与黄芩饮片提取液相比，大鼠口服牛黄解毒片混悬液后，黄芩苷及汉黄芩苷的首个吸收峰的吸收程度明显增强，远高于第2个吸收峰，致使黄芩苷及汉黄芩苷的Tmax分别降低了98%与72%。除此之外，与黄芩饮片提取液比较，大鼠口服牛黄解毒片混悬液后，血浆中汉黄芩苷的AUC0-t增加了76%，黄芩苷及汉黄芩苷的Cmax分别增加了141%与112%。牛黄解毒片复方配伍后显著提高了黄芩有效成分的吸收利用，加快了吸收速率。已有文献报道，雄黄与黄芩配伍，可通过降低细胞膜渗透性抑制黄芩苷、黄芩素的体内代谢，延长作用时间[21]。大黄与黄芩配伍，可以抑制炎症介质IL-6，IL-1，TNF-α的释放，从而提高黄芩的抗炎效果[22]。这些结果也进一步验证了复方配伍对黄芩主要活性成分存在显著影响的现象。本研究揭示了黄芩特征成分在配伍药物作用下的体内药代动力学行为，为指导黄芩临床合理用药及配伍相关研究提供参考依据。
基金
收起
  • * 国家自然科学基金资助项目(82104523)
  • 江苏省自然科学基金青年基金资助项目(BK20200843)
  • 南京中医药大学国家自然科学基金青年科学基金配套经费项目(XPT82104523)
文献
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2024年第44卷第7期
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doi: 10.16155/j.0254-1793.2023-0302
  • 首发时间：2026-03-13
  • 出版时间：2024-07-31
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  • 修回日期：2024-03-18
基金
* 国家自然科学基金资助项目(82104523)
江苏省自然科学基金青年基金资助项目(BK20200843)
南京中医药大学国家自然科学基金青年科学基金配套经费项目(XPT82104523)
作者信息
    1.天津药物研究院药业有限责任公司，天津 300301
    2.中国药科大学药物分析系，南京210009
    3.南京中医药大学，南京 210023

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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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