Article(id=1222469815210598731, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1222469808688451726, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2019-0515, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1561478400000, receivedDateStr=2019-06-26, revisedDate=1566316800000, revisedDateStr=2019-08-21, acceptedDate=null, acceptedDateStr=null, onlineDate=1769389116336, onlineDateStr=2026-01-26, pubDate=1576080000000, pubDateStr=2019-12-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1769389116336, onlineIssueDateStr=2026-01-26, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1769389116336, creator=13701087609, updateTime=1769389116336, updator=13701087609, issue=Issue{id=1222469808688451726, tenantId=1146029695717560320, journalId=1189982191388893191, year='2019', volume='54', issue='12', pageStart='2141', pageEnd='2352', issueExtLink='null', onlineDate='null', pubDate='1576080000000', pubDateStr='2019-12-12', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1769389114782, creator='13701087609', updateTime=1769389604971, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1222471864748859926, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1222469808688451726, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1222471864748859927, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1222469808688451726, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=2308, endPage=2315, ext={EN=ArticleExt(id=1222469817341305315, articleId=1222469815210598731, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=UHPLC quantification and brain permeability study of sinomenine and ligustrazine in CQM after single intravenous administration, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

Chuanxiong Qingfengteng mixture (CQM) is an analgesic developed based on clinical evidence and traditional Chinese medicine theory, which majorly consists of Ligusticum chuanxiong and Sinomenium acutum extracts. The current study aims to establish an UHPLC-UV method for the quantification of sinomenine and ligustrazine after CQM administration to rats, mice and cells, and to study the brain permeability of sinomenine and ligustrazine. The selectivity, linearity, accuracy, precision and stability of the established method demonstrated that it was suitable for the determination of sinomenine and ligustrazine in biological samples such as plasma, brain tissue and cellular fluid. After CQM was intravenously administered to rats and mice, both sinomenine and ligustrazine were detected in the brain from 5 min-2 h. The CSF/plasma partition coefficients (K_{p, C/P}) of each component were higher than those of brain tissue/plasma partition coefficient (K_{p, B/P}), the K_{p, C/P} and K_{p, B/P} of ligustrazine were higher than those of sinomenine. The concentrations between CSF and brain tissue were strongly correlated (Pearson's R>0.86, P < 0.001). The unbound fraction in plasma of sinomenine and ligustrazine was 78.92% and 34.07%, respectively. The plasma protein binding rates displayed concentration-independent behavior within their respective in vivo concentration ranges. After CQM co-cultured with Caco-2 cell monolayers, the apparent permeability coefficient (P_app) of sinomenine and ligustrazine were 1.30×10^-6 and 3.64×10^-6 cm·s^-1, respectively, following into the range of the intermediate and high permeability compounds. The efflux ratio (P_{app(basolateral→apical)}/P_{app(apical→basolateral)}) of sinomenine and ligustrazine were 0.67 and 0.85, respectively. When combined with P-glycoprotein inhibitor, the P_app of each component did not increase. In conclusion, the UHPLC-UV assay was successfully applied for the brain permeability study of CQM, the components of CQM can be quickly distributed to cerebrospinal fluid and pass through the blood-brain barrier. The brain permeability of ligustrazine is higher than that of sinomenine. The transmembrane transport of sinomenine and ligustrazine may not be affected by efflux transporters. All animal care and use complied with the Regulations for the Administration of Affairs Concerning Experimental Animals approved by the State Council of the People's Republic of China. All animal studies were implemented according to protocols, which were reviewed and approved by the Institutional Animal Care and Use Committee at Experimental Research Center, China Academy of Chinese Medical Sciences.

, authors=null, authorsList=Tao LI, Xiao-liang ZHAO, Ying-lan NIE, Yue JIAO, Yang LIU, Mei-yu ZHANG, Yu-juan LI, Zhi-guo WANG, Dan-qiao WANG, authorCompany=null, correspAuthors=Dan-qiao WANG, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2019 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, fund=null), CN=ArticleExt(id=1222469818838671978, articleId=1222469815210598731, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=CQ止痛复方中青藤碱和川芎嗪的脑通透性研究, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

建立给予CQ止痛复方（Chuanxiong Qingfengteng mixture，CQM）后大、小鼠血浆、脑组织及细胞液等生物样品中青藤碱和川芎嗪的UHPLC-UV定量分析方法，并研究这两种组分的脑通透性。分析方法经选择性、线性范围、准确度、精密度、稳定性等考察确证适合以上生物样品中青藤碱和川芎嗪的测定。大鼠和小鼠静脉注射CQM，5 min~2 h在脑脊液和脑组织均能检测到青藤碱和川芎嗪，且脑组织与脑脊液的浓度具有强烈的相关性（Pearson's R>0.86，P < 0.001）；其中，川芎嗪的脑组织/血浆分配系数高于青藤碱。血浆游离分数青藤碱为78.92%，川芎嗪为34.07%，且在各自浓度范围内血浆蛋白结合率无明显依赖性。Caco-2细胞孵育CQM，青藤碱和川芎嗪在细胞单层膜上表观渗透系数（P_app）分别为1.30和3.64×10^-6 cm·s^-1，属中通透性和高通透性化合物；联用P-糖蛋白（P-gp）抑制剂后，各组分P_app均未增加。上述结果表明CQM各组分能快速通过血脑屏障；川芎嗪的脑通透性高于青藤碱；各组分的跨膜转运可能不受P-gp等外排转运体的影响。本研究所有动物实验过程和动物关怀均遵守中华人民共和国《实验动物管理条例》，并得到中国中医科学院医学实验中心伦理委员会的批准。

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Int J Mol Sci, 2013, 14: 12873-12892., articleTitle=A novel perspective and approach to intestinal octreotide absorption: sinomenine-mediated reversible tight junction opening and its molecular mechanism, refAbstract=null), Reference(id=1222513656659698497, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469815210598731, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[20], rfOrder=19, authorNames=null, journalName=null, refType=null, unstructuredReference=Wang Y. Effect of Ligustrazine on the Blood-brain Barrier Model Permeability in vitro and Part of the Mechanism (川芎嗪对体外血脑屏障模型通透性的影响及部分作用机制)[D]. Heifei: Anhui University of Chinese Medicine, 2013., articleTitle=null, refAbstract=null), Reference(id=1222513656760361800, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469815210598731, doi=null, pmid=null, pmcid=null, year=2014, volume=69, issue=null, pageStart=48, pageEnd=54, url=http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=4d3498a42c12548e3dc4a314d5753c32, language=null, rfNumber=[21], rfOrder=20, authorNames=Chen Y, Zhang L, Lu X, journalName=Pharmazie, refType=null, unstructuredReference= Chen Y , Zhang L , Lu X et al . Sinomenine reverses multidrug resistance in bladder cancer cells via P-glycoprotein-dependent and independent manners[J]. 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Biomatrix	Component	Regression equation	r2	Linearity range/μg·mL-1
Plasma	Sinomenine	Y = 2 928.9X - 88.1	0.990	0.10-10
	Ligustrazine	Y = 10 120.0 X - 809.6	0.999	0.05-20
Brain	Sinomenine	Y = 3 210.0 X - 497.3	0.990	0.10-10
	Ligustrazine	Y = 10 400.0 X - 843.3	0.994	0.05-20
Cellular fluid	Sinomenine	Y = 3 866.4 X + 17.6	0.999	0.05-5
	Ligustrazine	Y = 11 521.0 X + 6.0	1.000	0.02-5

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Calibration curve parameters of sinomenine and ligustrazine in rat plasma, brain and cellular fluid samples

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Biomatrix	Component	Regression equation	r2	Linearity range/μg·mL-1
Plasma	Sinomenine	Y = 2 928.9X - 88.1	0.990	0.10-10
	Ligustrazine	Y = 10 120.0 X - 809.6	0.999	0.05-20
Brain	Sinomenine	Y = 3 210.0 X - 497.3	0.990	0.10-10
	Ligustrazine	Y = 10 400.0 X - 843.3	0.994	0.05-20
Cellular fluid	Sinomenine	Y = 3 866.4 X + 17.6	0.999	0.05-5
	Ligustrazine	Y = 11 521.0 X + 6.0	1.000	0.02-5

), ArticleFig(id=1222513653534941822, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469815210598731, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=

Component	AUCcsf (0.083-4 h) /h·μg·mL-1	AUCbrain (0.083-4 h) /h·μg·mg-1	AUCplasma(0.083-4 h) /h·μg·mL-1	Kp, C/P/%	Kp, B/P/%	fu/% (n = 12)
Sinomenine	1.21	0.55	3.97	30.52	13.83	78.92 ± 3.44
Ligustrazine	6.67	3.26	13.25	50.35	24.59	34.07 ± 1.94

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AUC, K_p and f_u results of sinomenine and ligustrazine after single intravenous administration of Chuanxiong Qingfengteng mixture at the dosage of 25 mg·kg^-1 in rats. n = 3, $\bar{x}\pm s$

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Component	AUCcsf (0.083-4 h) /h·μg·mL-1	AUCbrain (0.083-4 h) /h·μg·mg-1	AUCplasma(0.083-4 h) /h·μg·mL-1	Kp, C/P/%	Kp, B/P/%	fu/% (n = 12)
Sinomenine	1.21	0.55	3.97	30.52	13.83	78.92 ± 3.44
Ligustrazine	6.67	3.26	13.25	50.35	24.59	34.07 ± 1.94

), ArticleFig(id=1222513653774017169, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469815210598731, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=

Component	Papp (×10-6 cm·s-1)				Efflux ratio
	Apical→basolateral			Basolateral→apical
	CQM	Verapamil+CQM		CQM
Sinomenine	1.30 ± 0.19	1.19 ± 0.15		0.87 ± 0.09	0.67
Ligustrazine	3.64 ± 0.26	3.06 ± 0.17**		3.08 ± 0.25	0.85

), ArticleFig(id=1222513653912429209, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469815210598731, language=CN, label=Table 3, caption=

Apparent permeability for sinomenine and ligustrazine of Chuanxiong Qingfengteng mixture (CQM) in Caco-2 cell monolayers. ^**P < 0.01 vs CQM group. n = 4, $\bar{x}\pm s$

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Component	Papp (×10-6 cm·s-1)				Efflux ratio
	Apical→basolateral			Basolateral→apical
	CQM	Verapamil+CQM		CQM
Sinomenine	1.30 ± 0.19	1.19 ± 0.15		0.87 ± 0.09	0.67
Ligustrazine	3.64 ± 0.26	3.06 ± 0.17**		3.08 ± 0.25	0.85

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