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Article(id=1198652617544008247, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1198652605778985059, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2023-0481, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1681833600000, receivedDateStr=2023-04-19, revisedDate=1684684800000, revisedDateStr=2023-05-22, acceptedDate=null, acceptedDateStr=null, onlineDate=1763710653911, onlineDateStr=2025-11-21, pubDate=1691769600000, pubDateStr=2023-08-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1763710653911, onlineIssueDateStr=2025-11-21, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1763710653911, creator=13701087609, updateTime=1763710653911, updator=13701087609, issue=Issue{id=1198652605778985059, tenantId=1146029695717560320, journalId=1189982191388893191, year='2023', volume='58', issue='8', pageStart='0', pageEnd='2540', issueExtLink='null', onlineDate='null', pubDate='1691769600000', pubDateStr='2023-08-12', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1763710651106, creator='13701087609', updateTime=1763710739504, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1198652976601596347, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1198652605778985059, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1198652976601596348, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1198652605778985059, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=2448, endPage=2453, ext={EN=ArticleExt(id=1198652618630333032, articleId=1198652617544008247, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=LC-MS/MS method for the determination of an anti-tumor compound C17 in nude mice plasma and its application to a pharmacokinetic study, columnId=null, journalTitle=Acta Pharmaceutica Sinica, columnName=null, runingTitle=null, highlight=null, articleAbstract=

C17 is an orally available anti-tumor compound inhibiting cancer stem cell (CSC). In this study, a stable, sensitive and simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was established and validated, and was further applied to a pharmacokinetic study in nude mice receiving C17 by gavage. Using propranolol as the internal standard, the plasma samples were pre-treated by precipitation with methanol and analyzed on an Intersil C8-3 column (100 mm × 2.1 mm, 3 μm), and gradient elution was performed with a mobile phase consisting of 0.1% formic acid aqueous and solution mixed up by 90% isopropanol and 10% acetonitrile. The analyte was detected by a triple quadrupole tandem mass spectrometer, and multiple reaction monitoring was employed to select C17 at m/z 439.3/247.1 and propranolol at m/z 260.2/116.2 in the positive ion mode. The calibration curves were linear (r > 0.995) over the range of 5-800 ng·mL-1. The intra- and inter-day precisions and accuracies were 7.42%-13.22% and -8.99%-8.81% respectively. The method was successfully applied to a PK study in nude mice administered with a single oral dose of 50 mg·kg-1 C17, and the PK data were analyzed with non-linear mixed effect model (NONMEM). Two separated absorption peaks were found in the PK curve of C17, and a two-compartment model with two sequential first-order absorption rate was utilized to describe the PK properties of C17, and the model could provide insights into the physiological process and exposure of C17 in nude mice. All animal experiments were in strict accordance with the regulations of the Biomedical Ethics Committee of Peking University.

, authors=null, authorsList=Qing-yu YAO, Yao-yao FENG, Xiao-xue YAN, Guo-shu CHEN, Tian-yan ZHOU, authorCompany=null, correspAuthors=Guo-shu CHEN, Tian-yan ZHOU, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2023 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=1198652620995920767, articleId=1198652617544008247, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=LC-MS/MS测定裸鼠血浆中抗肿瘤化合物C17的分析方法及其在药物动力学研究中的应用, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

C17是一种具有抗肿瘤干细胞作用的可口服的抗肿瘤化合物。本研究首先建立了测定裸鼠血浆中C17的LC-MS/MS分析方法, 该方法以普萘洛尔作为内标物, 采用甲醇沉淀蛋白法对血浆样品进行处理。采用Intersil C8-3色谱柱(100 mm × 2.1 mm, 3 μm) 进行色谱分离, 以0.1%的甲酸水溶液和90%异丙醇与10%乙腈的混合溶液为流动相进行梯度洗脱。采用API 4000 Q-TRAP三重四级杆质谱的多反应监测扫描模式进行检测, 正离子模式下C17和内标物的离子对质核比分别为439.3/247.1和260.2/116.2。标准曲线的线性范围为5~800 ng·mL-1 (r > 0.995), 方法的日内/日间精密度和准确性分别在7.42%~13.22%和-8.99%~8.81%间, 所建方法稳定、灵敏且简单易行。之后, 使用该方法测定裸鼠C17单次灌胃给药50 mg·kg-1剂量下的血药浓度, 并采用非线性混合效应模型(NONMEM) 进行PK建模分析。C17灌胃给药后出现两个互相分离的吸收峰, 采用带有两个一级速率顺序吸收过程的二室模型对其PK行为进行描述, 为研究C17在裸鼠的体内过程和暴露打下基础。所有动物实验均严格遵循北京大学生物医学伦理委员会的规定。

, authors=

#共同第一作者.

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*周田彦, Tel: 86-10-82801717, E-mail: ;
陈国术, Tel: 86-20-39366902, E-mail:
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Anticancer Drugs, 2008, 19: 721-727., articleTitle=Antitumor activity and biodistribution of cisplatin nanocapsules in nude mice bearing human ovarian carcinoma xenografts, refAbstract=null)], funds=[Fund(id=1198960117879243062, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652617544008247, awardId=82073919, language=CN, fundingSource=国家自然科学基金资助项目(82073919), fundOrder=null, country=null), Fund(id=1198960118042820937, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652617544008247, awardId=7192100, language=CN, fundingSource=北京市自然科学基金资助项目(7192100), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1198960112321790676, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652617544008247, xref=null, ext=[AuthorCompanyExt(id=1198960112330179287, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652617544008247, companyId=1198960112321790676, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1. 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A: Chromatogram of blank plasma; B: Chromatogram of blank plasma spiked with C17 (500 ng·mL-1) and internal standard (14.4 μg·mL-1); C: Chromatogram of plasma collected 5 min after a single oral dose of 50 mg·kg-1 of C17

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Parameter Estimate (RSE) SIR result
Median 95% confidence interval
ka1 /h-1 14.3 (29.5%) 14.4 6.83-26.8
ka2 /h-1 0.918 (35.5%) 0.921 0.469-1.55
CL/F /L·kg-1·h-1 34.1 (9.1%) 34.0 28.5-40.8
Q/F /L·kg-1·h-1 29.5 (42.7%) 29.4 15.7-57.0
Vc/F /L·kg-1 42.4 (14.5%) 42.5 30.6-55.8
Vp/F /L·kg-1 188 (30.3%) 188 132-304
f 0.359 (11.1%) 0.357 0.280-0.452
tlag /h 2.85 (2.8%) 2.85 2.74-2.95
Residual error σ /% 46.5 (11.6%) 46.5 36.7-58.0
), ArticleFig(id=1198960117598224665, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652617544008247, language=CN, label=Table 1, caption=

PK parameters of C17 in nude mice and SIR results. SIR: Sampling importance resampling

, figureFileSmall=null, figureFileBig=null, tableContent=
Parameter Estimate (RSE) SIR result
Median 95% confidence interval
ka1 /h-1 14.3 (29.5%) 14.4 6.83-26.8
ka2 /h-1 0.918 (35.5%) 0.921 0.469-1.55
CL/F /L·kg-1·h-1 34.1 (9.1%) 34.0 28.5-40.8
Q/F /L·kg-1·h-1 29.5 (42.7%) 29.4 15.7-57.0
Vc/F /L·kg-1 42.4 (14.5%) 42.5 30.6-55.8
Vp/F /L·kg-1 188 (30.3%) 188 132-304
f 0.359 (11.1%) 0.357 0.280-0.452
tlag /h 2.85 (2.8%) 2.85 2.74-2.95
Residual error σ /% 46.5 (11.6%) 46.5 36.7-58.0
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LC-MS/MS测定裸鼠血浆中抗肿瘤化合物C17的分析方法及其在药物动力学研究中的应用
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姚庆宇 1, # , 冯瑶瑶 1, # , 严晓雪 2 , 陈国术 2, * , 周田彦 1, *
药学学报 | 研究论文 2023,58(8): 2448-2453
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药学学报 |研究论文 2023 , 58 (8) : 2448 -2453
LC-MS/MS测定裸鼠血浆中抗肿瘤化合物C17的分析方法及其在药物动力学研究中的应用
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姚庆宇1, #, 冯瑶瑶1, #, 严晓雪2, 陈国术2, * , 周田彦1, *
作者信息
  • 1.北京大学医学部药学院, 分子药剂学与新药递送系统北京市重点实验室, 北京 100191
  • 2.广州大学化学化工学院, 广东 广州 510006
通讯作者:
*周田彦, Tel: 86-10-82801717, E-mail: ;
陈国术, Tel: 86-20-39366902, E-mail:
LC-MS/MS method for the determination of an anti-tumor compound C17 in nude mice plasma and its application to a pharmacokinetic study
Qing-yu YAO1, Yao-yao FENG1, Xiao-xue YAN2, Guo-shu CHEN2, * , Tian-yan ZHOU1, *
Affiliations
  • 1. Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Health Science Center, Peking University, Beijing 100191, China
  • 2. School of Chemistry and Chemical Engineering, Guangzhou University, Guangzhou 510006, China
出版时间: 2023-08-12 doi: 10.16438/j.0513-4870.2023-0481
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摘要
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C17是一种具有抗肿瘤干细胞作用的可口服的抗肿瘤化合物。本研究首先建立了测定裸鼠血浆中C17的LC-MS/MS分析方法, 该方法以普萘洛尔作为内标物, 采用甲醇沉淀蛋白法对血浆样品进行处理。采用Intersil C8-3色谱柱(100 mm × 2.1 mm, 3 μm) 进行色谱分离, 以0.1%的甲酸水溶液和90%异丙醇与10%乙腈的混合溶液为流动相进行梯度洗脱。采用API 4000 Q-TRAP三重四级杆质谱的多反应监测扫描模式进行检测, 正离子模式下C17和内标物的离子对质核比分别为439.3/247.1和260.2/116.2。标准曲线的线性范围为5~800 ng·mL-1 (r > 0.995), 方法的日内/日间精密度和准确性分别在7.42%~13.22%和-8.99%~8.81%间, 所建方法稳定、灵敏且简单易行。之后, 使用该方法测定裸鼠C17单次灌胃给药50 mg·kg-1剂量下的血药浓度, 并采用非线性混合效应模型(NONMEM) 进行PK建模分析。C17灌胃给药后出现两个互相分离的吸收峰, 采用带有两个一级速率顺序吸收过程的二室模型对其PK行为进行描述, 为研究C17在裸鼠的体内过程和暴露打下基础。所有动物实验均严格遵循北京大学生物医学伦理委员会的规定。

液相色谱-串联质谱  /  裸鼠  /  药物动力学  /  非线性混合效应模型

C17 is an orally available anti-tumor compound inhibiting cancer stem cell (CSC). In this study, a stable, sensitive and simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was established and validated, and was further applied to a pharmacokinetic study in nude mice receiving C17 by gavage. Using propranolol as the internal standard, the plasma samples were pre-treated by precipitation with methanol and analyzed on an Intersil C8-3 column (100 mm × 2.1 mm, 3 μm), and gradient elution was performed with a mobile phase consisting of 0.1% formic acid aqueous and solution mixed up by 90% isopropanol and 10% acetonitrile. The analyte was detected by a triple quadrupole tandem mass spectrometer, and multiple reaction monitoring was employed to select C17 at m/z 439.3/247.1 and propranolol at m/z 260.2/116.2 in the positive ion mode. The calibration curves were linear (r > 0.995) over the range of 5-800 ng·mL-1. The intra- and inter-day precisions and accuracies were 7.42%-13.22% and -8.99%-8.81% respectively. The method was successfully applied to a PK study in nude mice administered with a single oral dose of 50 mg·kg-1 C17, and the PK data were analyzed with non-linear mixed effect model (NONMEM). Two separated absorption peaks were found in the PK curve of C17, and a two-compartment model with two sequential first-order absorption rate was utilized to describe the PK properties of C17, and the model could provide insights into the physiological process and exposure of C17 in nude mice. All animal experiments were in strict accordance with the regulations of the Biomedical Ethics Committee of Peking University.

LC-MS/MS  /  nude mice  /  pharmacokinetics  /  non-linear mixed effect model
姚庆宇, 冯瑶瑶, 严晓雪, 陈国术, 周田彦. LC-MS/MS测定裸鼠血浆中抗肿瘤化合物C17的分析方法及其在药物动力学研究中的应用. 药学学报, 2023 , 58 (8) : 2448 -2453 . DOI: 10.16438/j.0513-4870.2023-0481
Qing-yu YAO, Yao-yao FENG, Xiao-xue YAN, Guo-shu CHEN, Tian-yan ZHOU. LC-MS/MS method for the determination of an anti-tumor compound C17 in nude mice plasma and its application to a pharmacokinetic study[J]. Acta Pharmaceutica Sinica, 2023 , 58 (8) : 2448 -2453 . DOI: 10.16438/j.0513-4870.2023-0481
正文
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肿瘤干细胞(cancer stem-like cell, CSC) 是一类具有自我更新能力和分化潜能的肿瘤细胞, 与肿瘤的转移、耐药和复发具有密切关系[1, 2]。本团队前期研究合成并筛选得到了一系列结构上具有N-芳基哌嗪结构的化合物, 在体内外呈现出较好的抗CSC作用, 并在乳腺癌、非小细胞肺癌等荷瘤动物模型中有效抑制了肿瘤转移, 具有作为针对CSC靶向治疗候选化合物的潜力[3-5]。
其中, 化合物C17 (结构见图 1A) 口服给药有效, 并能够明显降低乳腺癌及胰腺癌中CSC比例, 抑制肿瘤细胞克隆形成及体内成瘤性, 抑制乳腺癌的肺转移, 并显著增强靶向药物舒尼替尼的抗肿瘤药效[6, 7]。上述结果初步证实了C17的抗CSC效应, 但其经过灌胃后的药物动力学(pharmacokinetics, PK) 行为尚有待探索。由于临床前抗肿瘤研究通常采用荷瘤裸鼠动物模型, 对C17在裸鼠体内的PK性质的探索将有助于今后构建其药物动力学/药效动力学(pharmacokinetic/pharmacodynamic, PK/PD) 模型, 进而推动其向临床应用转化。因此, 首先需要建立C17在裸鼠血浆中的分析方法, 从而准确测定其血药浓度。
本研究旨在采用液相色谱-串联质谱(liquid chromatography-tandem mass spectrometric, LC-MS/MS) 方法, 建立并验证一种稳定、灵敏且简单易行的C17在裸鼠血浆中的分析方法; 进而测定灌胃给药后裸鼠体内C17血药浓度的时间过程, 对其PK性质进行研究。
材料与方法
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试剂
化合物C17 (纯度 > 95%, 由广州大学陈国术副教授课题组合成); 内标(internal standard, IS) 为盐酸普萘洛尔(结构见图 1B, 纯度 > 98%, 中国武汉远成共创科技有限公司); 1, 2-丙二醇(分析纯, 中国北京市通广精细化工公司); 甲醇(HPLC级, 美国Thermo Fisher Scientic公司); 蒸馏水(中国广州屈臣氏食品饮料有限公司); 肝素钠(中国上海麦克林生化科技有限公司)。
仪器
LC-20ADXR-HPLC系统和Intersil C8-3色谱柱(日本岛津公司); API 4000 Q-TRAP型液相色谱-质谱联用仪(美国AB Sciex公司); D3024R型高速冷冻离心机(美国SCILOGEX公司); 飞鸽TGL-16G型离心机(中国上海安亭科学仪器厂); QL-866型涡旋混合器(中国江苏海门其林贝尔仪器有限公司)。
实验动物
SPF级7~8周龄(20~22 g) 的nu/nu雌性裸鼠购自北京维通利华实验动物技术有限公司, 饲养于独立通风笼具中, 温度恒定为22~25 ℃, 湿度恒定为50%~60%, 每天交替进行12 h光照/12 h黑暗, 动物可自由饮水取食。所有动物实验均严格按照北京大学生物医学伦理委员会的规定进行。
色谱条件
Intersil C8-3色谱柱(100 mm × 2.1 mm, 3 μm)。流动相: 流动相A为甲酸(0.1%) 水溶液, 流动相B为异丙醇(90%) 与乙腈(10%) 的混合溶液; 柱温: 40 ℃; 流速: 0.3 mL·min-1; 进样体积: 5 μL; 梯度洗脱条件: 0~1.0 min, 90% A; 1.0~3.0 min, 90%~0% A; 3.0~5.5 min, 0% A; 5.5~6 min, 0~90% A; 6~8 min, 90% A。
质谱条件
工作模式为多反应监测扫描(multiple reaction monitoring, MRM); 电喷雾离子源: 正离子模式; 气帘气: 25 psi (1 psi ≈ 6.9 kPa); 离子喷雾电压: 5 500 V; 离子源温度: 450 ℃; 离子源气1: 50 psi; 离子源气2: 55 psi; 碰撞气: 氮气; C17离子对的质荷比(m/z) 为439.3/247.1, 去簇电压为110 eV, 碰撞电压为36 eV; IS离子对的m/z为260.2/116.2, 去簇电压为60 eV, 碰撞电压为26 eV。
标准样品、质控样品配制
精密称取一定量的C17和IS, 分别用适量甲醇溶解, 配制成浓度为500 μg·mL-1的C17和IS储备液。用甲醇将C17储备液进行梯度稀释, 得到浓度分别为0.1、0.3、1、4、10、16 μg·mL-1的C17工作液, 并用甲醇将IS储备液稀释为14.4 μg·mL-1的IS工作液。取95 μL空白血浆, 依次加入5 μL不同浓度的C17工作液, 涡旋2 min, 得到C17浓度分别为5、15、50、200、500、800 ng·mL-1的标准样品; 取95 μL空白血浆, 依次加入5 μL 0.3、10、16 μg·mL-1的C17工作液, 涡旋2 min, 分别得到C17低浓度(15 ng·mL-1)、中浓度(500 ng·mL-1)、高浓度(800 ng·mL-1) 的质控(quality control, QC) 样品。
血浆样品处理
标准样品、QC样品  向上述100 μL标准样品和QC样品加入5 μL的IS工作液, 涡旋2 min后, 加入500 μL甲醇, 涡旋2 min, 在4 ℃、13 000 r·min-1下离心15 min, 吸取80 μL上清液, 迅速加入进样小瓶中, 上机检测。
含药待测血浆样品  向100 μL待测血浆样品中加入5 μL IS工作液, 涡旋2 min后, 加入500 μL甲醇, 涡旋2 min, 后续操作与标准样品、QC样品相同。
方法学验证
根据美国食品药品监督管理局(FDA) 指南的相关要求进行方法学验证[8]。
专属性  通过对比空白血浆、加入一定浓度的C17和IS的空白血浆以及裸鼠给药后收集并加入IS的血浆样品的LC-MS/MS图谱, 考察本方法的专属性。
标准曲线和最低定量限(lower limit of quantitation, LLOQ)  以C17的浓度为横坐标(X), C17与IS的峰面积比值为纵坐标(Y), 并以权重因子W = 1/x的形式进行加权, 采用最小二乘法绘制标准曲线。标准曲线的下限(5 ng·mL-1) 为LLOQ, 要求其信噪比(signal/noise, S/N) 不小于10。
精密度和准确度  制备C17不同浓度QC样品, 每个浓度平行制备5份, 在1天内对每个样品重复测定3次, 考察日内精密度和准确度; 连续3天分别平行制备5份各浓度的QC样品并进样检测, 考察日间精密度和准确度。
回收率  分别制备C17不同浓度QC样品, 处理样品时将空白血浆改为甲醇, 制备相同浓度的含药甲醇溶液, 继续处理样品, 进样检测, 记录C17的峰面积。回收率为C17在QC样品中的峰面积与甲醇溶液中峰面积的比值。
基质效应  取一定量空白血浆, 按照前述方法处理加入甲醇沉淀蛋白后, 在4 ℃、13 000 r·min-1下离心15 min, 吸取上清液。用该上清液替代空白血浆制备C17不同浓度QC的含药溶液, 每个浓度平行制备5份, 处理样品后进样检测; 同时用甲醇替代空白血浆制备相同浓度的含药甲醇溶液, 处理样品后进样检测。基质效应为C17在上清液中的峰面积与甲醇溶液中峰面积的比值。
稳定性  制备C17不同浓度QC样品, 分别置于室温下12 h, -80 ℃冰箱中2周, 以及反复冻融3次, 考察样品在不同条件下的稳定性。
稀释效应  用空白血浆将C17稀释至8 000 ng·mL-1, 之后用空白血浆进一步稀释至800 ng·mL-1, 处理样品后进样检测, 并根据标准曲线计算实测浓度, 与理论值浓度进行比较。
药物动力学研究
裸鼠随机分为12组, 每组3只, 分别用于12个时间点的血浆样品采集。给药前禁食至少6 h, 期间可自由饮水。将C17用1, 2丙二醇溶解, 配制成浓度为10 mg·mL-1的C17溶液, 给药前称量裸鼠体重, 以50 mg·kg-1的剂量灌胃给药, 分别于给药前及给药后0.083、0.25、0.5、1、2、3、4、6、10、15、24 h摘除裸鼠眼球取血, 收集于预先经肝素化处理的1.5 mL离心管中, 采集完成后, 立即在4 000 r·min-1条件下离心10 min, 吸取上清液于1.5 mL离心管中, 置于-80 ℃冰箱保存。待收集到所有时间的样品后, 将待测样品从-80 ℃冰箱取出置于冰上缓慢融化, 按照前述方法处理样品后上机测定。测得的PK数据采用非线性混合效应模型(non-linear mixed effect modeling, NONMEM, v7.4.0, 美国ICON Development Solutions公司) 软件进行建模分析, 算法为带有相互作用的一级条件评估法(first-order conditional estimation with interaction, FOCEI)。根据模型是否收敛、目标函数值(objective function value, OFV) 的变化、参数是否合理以及模型的拟合优度(goodness of fit, GOF) 等对所建立的模型进行评价与比较, 从中得到最终PK模型。
结果
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1 方法学验证
1.1 专属性
将裸鼠空白血浆、空白血浆中加入C17和IS、裸鼠给药C17后采集血浆经样品处理并进样检测后, 各样品所得到图谱见图 2。C17呈现两个基线相分离的峰, 保留时间分别为0.9和1.4 min, IS保留时间为3.6 min。在该测定条件下, C17和IS的出峰位置无血浆中内源性物质的干扰, 表明该方法的专属性良好。
1.2 标准曲线和LLOQ
以C17的浓度为横坐标(X), C17两个峰面积之和与IS峰面积比值为纵坐标(Y), 并以权重因子W = 1/x的形式进行加权, 采用最小二乘法拟合标准曲线, 线性范围为5~800 ng·mL-1, 线性回归方程为: Y = 0.001 907 X + 0.006 777, 相关系数r > 0.995, 表明在5~800 ng·mL-1内线性关系良好。最低定量限为5 ng·mL-1, 且在该浓度下信噪比大于10, 5个平行样品的RSD为6.10%, RE为12.22%, 符合FDA生物样品的分析要求。
1.3 精密度和准确度
各浓度的QC样品日内和日间相对标准差(relative standard deviation, RSD) 均小于15%, 相对误差(relative error, RE) 均在±15%以内, 表明该分析方法的精密度和准确度较好。
1.4 回收率与基质效应
三个QC浓度下的回收率在81.12%~88.86%之间, RSD均小于15%, 基质效应为77.76%~89.31%, RSD均小于15%, 表明基质效应略有影响, 但总体能够满足测定需要。
1.5 稳定性
各浓度QC样品在三种不同条件下, 各浓度QC样品的RSD均小于15%, RE均在±15%以内, 方法稳定性良好。
1.6 稀释效应
将C17浓度为8 000 ng·mL-1的血浆样品用空白血浆稀释10倍后, 进样检测, 5个平行样品的RSD为8.67%, RE为-3.18%, 表明该分析方法可以用于C17更高浓度样品的分析。
2 C17在裸鼠血浆中的药时曲线和PK模型
2.1 C17在裸鼠血浆中的药时曲线
C17以50 mg·kg-1的剂量灌胃给药后, 裸鼠血浆中的血药浓度随时间的变化见图 3。C17在裸鼠体内在0.25和4 h附近分别出现两个明显的吸收峰, 经过第二个吸收峰之后C17逐渐被消除, 24 h后血药浓度降低至峰浓度的1/10以下。
2.2 PK模型
采用NONMEM软件拟合C17在裸鼠体内的PK行为。最终PK模型假设药物以不同吸收速率先后在两个部位进行吸收, 采用两个一级速率顺序吸收过程的二室模型对PK数据进行拟合, 模型结构见图 4。
在该模型中, 假设药物以一级吸收速率从两个吸收隔室先后进入中央隔室, 并分布到外周隔室, 药物以线性形式从中央室消除。其中, X0为给药剂量; Xa1和Xa2分别为两个吸收部位的药物量; f为经Xa1隔室吸收的药物量占药物总量的比例; Xa1隔室吸收起始时间为零时刻, Xa2隔室吸收起始时间相较于Xa1隔室吸收的滞后时间为tlag; ka1和ka2分别为药物经Xa1隔室和Xa2隔室的一级吸收速率常数; F为C17的生物利用度; Xc和Xp分别为C17在中央室和外周室的药物量; Vc和Vp分别为C17在中央室和外周室的表观分布容积; CL为药物在中央室的清除率; Q为隔室间清除率; Cc和Cp分别为中央室和外周室的药物浓度, 方程式1~6如下:
$\frac{\mathrm{d}{X}_{\mathrm{a}1}}{\mathrm{d}t}=-{k}_{\mathrm{a}1}·{X}_{0}·f$
$\frac{\mathrm{d}{X}_{\mathrm{a}2}}{\mathrm{d}t}=-{k}_{\mathrm{a}2}·{X}_{0}·\left(1-f\right),t\ge {t}_{\mathrm{l}\mathrm{a}\mathrm{g}}$
$\begin{array}{l}\frac{\mathrm{d}{X}_{\mathrm{c}}}{\mathrm{d}t}={k}_{\mathrm{a}1}·{X}_{0}·f · F+{k}_{\mathrm{a}2}·{X}_{0}·\left(1-f\right)·F-{X}_{\mathrm{c}}·\frac{\mathrm{C}\mathrm{L}}{{V}_{\mathrm{c}}}-\\ {X}_{\mathrm{c}}·\frac{Q}{{V}_{\mathrm{c}}}+{X}_{\mathrm{p}}·\frac{Q}{{V}_{\mathrm{p}}},{X}_{\mathrm{C}}\left(0\right)=0\mathrm{ }\mathrm{ }\mathrm{ }\mathrm{ }\mathrm{ }\mathrm{ }\mathrm{ }\mathrm{ }\end{array}$
$\frac{\mathrm{d}{X}_{\mathrm{p}}}{\mathrm{d}t}={X}_{\mathrm{c}}·\frac{Q}{{V}_{\mathrm{c},}}-{X}_{\mathrm{p}}·\frac{Q}{{V}_{\mathrm{p}}},{X}_{\mathrm{P}}\left(0\right)=0\mathrm{ }\mathrm{ }\mathrm{ }\mathrm{ }\mathrm{ }$
${C}_{\mathrm{c}}=\frac{{X}_{\mathrm{c}}}{{V}_{\mathrm{c}}}$
${C}_{\mathrm{p}}=\frac{{X}_{\mathrm{p}}}{{V}_{\mathrm{p}}}$
模型参数和重要性重采样(sampling importance resampling, SIR) 结果见表 1, 模型参数整体较为稳健。有35.9%的C17经过Xa1隔室迅速被吸收, 而2.85 h后其余C17经过Xa2隔室吸收进入中央隔室, 与实际观测结果比较接近。Xa1隔室的吸收速率常数ka1为14.3 h-1, 显著高于Xa2隔室的吸收速率常数ka2 (0.918 h-1), 与实际观测到的第一个吸收峰更为尖锐陡峭相吻合, 模型结果较为合理。
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通过靶向CSC来克服肿瘤的转移、耐药、复发等问题, 近年来逐渐被认为是一种具有潜力的肿瘤治疗策略而被广泛研究[9]。由本课题组与广州大学陈国术课题组共同设计并开发了一系列通过靶向DR进而发挥抗CSC作用的化合物, 其中C17能够显著降低CSC比例, 进而发挥抑制肿瘤的发生、转移等功能[6, 7]。本研究首次建立了裸鼠血浆中测定C17的LC-MS/MS分析方法, 并进行了方法学验证, 不仅能够为C17后续PK及PK/PD研究提供基础, 也能够为后续结构类似的同系列化合物的生物分析提供参考。
在本研究的色谱条件下, C17被洗脱为两个基线分离的峰。尽管尝试过包括甲醇、乙腈、异丙醇等在内的多种不同的流动相和配比, 以及不同的洗脱条件, 但C17始终不能以单峰形式出现。考虑到本研究所使用的C17纯度大于95%, 且在当前液质条件下两个峰的峰面积之比较为稳定, 因此由于杂质导致C17出现两个峰的可能性较低。从C17的化学结构分析(图 1A), 其哌嗪环中N原子上的取代基一般倾向于形成平伏键, 但也有可能形成直立键并与邻近的-NH-形成氢键, 因此推测C17在液质中出现双峰可能是由于存在两种不同形式的异构体。类似的情况在四氢姜黄素的LC-MS/MS检测中也有报道, 四氢姜黄素由于存在酮-烯醇互变异构体, 导致在相同的质谱条件下会出现两个相互分离的吸收峰, 因此本研究中采用类似的方法, 采用两个峰面积之和对C17进行定量[10, 11], 并通过了方法学验证, 能够满足生物样品测定的需求。未来将进一步对C17潜在的异构体进行探究和确认。
基于验证通过的LC-MS/MS方法, 测定C17灌胃给药后裸鼠体内的血药浓度, 得到药时曲线。由于裸鼠血容量较少, 无法对同一只动物在不同时间点连续采血, 每只裸鼠仅能提供一个时间点的血药浓度数据, 模型估算时无法区分个体间变异(inter-individual variability, IIV) 和个体内变异, 因此在采用NONMEM建立PK模型的时候将所有参数的IIV都固定为0, 由于最终的残差实际上是IIV和个体内变异的总和, 因此模型具有较大的残差变异[12, 13]。此外, 在建模时分别尝试了比例型、加和型以及混合型的残差模型。最终, 基于模型的OFV、拟合结果以及参数的合理性, 选择比例型残差模型。
C17在裸鼠血浆中的药时曲线呈现了两个吸收峰, 这一现象在多种药物中存在, 并可能由不同生理机制导致。本研究中为排除食物对药物吸收的影响, 裸鼠在给药后4 h内仍处于禁食状态, 而第二个吸收峰在给药后2 h附近已开始出现, 因此由于肠肝循环或者胃排空导致C17出现双吸收峰的可能性较低[14, 15]。对本研究中的C17而言, 可能的原因是胃肠道中存在两个不同的吸收部位, 或者由于P-糖蛋白等转运体将吸收的药物排出、药物再次由胃肠道吸收入血, 从而呈现出两次不连续的吸收过程[16-18]。因此, 假设C17分别以不同的吸收速率先后分两部分被吸收进入中央隔室, 并在建模时分别尝试了零级速率与一级速率同时吸收、零级速率与一级速率顺序吸收、两个一级速率顺序吸收等模型结构, 最终根据模型拟合效果及参数合理性, 选择了两个一级速率顺序吸收过程的二室模型对PK数据进行描述。目前的模型结构能够描述两个位点进行吸收或P-糖蛋白等转运体外排作用导致的再次吸收, 从而对C17的吸收过程较好地进行经验性描述。而C17吸收过程中形成双峰的生理机制, 仍有待后续研究的进一步探索和确证。
作为C17首次在裸鼠上进行的PK研究, 本研究仅进行了50 mg·kg-1单一剂量给药, 且每个时间点动物数为3只, 这是本研究的一个局限性。同时, 由于裸鼠的血液量有限, 每只裸鼠只能贡献一个数据点的血浆样品, 每次采样需要处死动物, 所以每个时间点处死3只裸鼠, 这在抗癌药物的临床前PK研究中通常是可接受的[13, 19, 20]。在未来的研究中, 将会进行更多剂量组及更多动物的研究, 以进一步考察其不同剂量下体内暴露量与药效之间的关系以及不同剂量下生物利用度是否存在差异, 对当前研究结果进行验证, 并在信息更为丰富的数据集中继续优化模型。
总之, 本研究建立了能够测定抗肿瘤化合物C17在裸鼠血浆内浓度的LC-MS/MS分析方法, 该方法具有简便、灵敏、稳定的特点, 并通过了方法学验证。应用该方法在裸鼠体内进行了PK研究, C17灌胃给药后在裸鼠体内的PK特征可以用具有两个一级速率顺序吸收过程的二室模型进行描述。当前研究结果将为C17后续的PK/PD研究及转化应用提供基础。
作者贡献: 周田彦和陈国术设计实验; 冯瑶瑶、姚庆宇和严晓雪进行实验; 姚庆宇、冯瑶瑶和进行数据分析; 姚庆宇进行文章撰写。
利益冲突: 本文作者之间无利益冲突。
基金
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  • 国家自然科学基金资助项目(82073919)
  • 北京市自然科学基金资助项目(7192100)
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2023年第58卷第8期
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doi: 10.16438/j.0513-4870.2023-0481
  • 接收时间：2023-04-19
  • 首发时间：2025-11-21
  • 出版时间：2023-08-12
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  • 收稿日期：2023-04-19
  • 修回日期：2023-05-22
基金
国家自然科学基金资助项目(82073919)
北京市自然科学基金资助项目(7192100)
作者信息
    1.北京大学医学部药学院, 分子药剂学与新药递送系统北京市重点实验室, 北京 100191
    2.广州大学化学化工学院, 广东 广州 510006

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*周田彦, Tel: 86-10-82801717, E-mail: ;
陈国术, Tel: 86-20-39366902, E-mail:
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