Development and validation of a sensitive and rapid UHPLC-MS/MS method for the simultaneous quantification of the common active and inactive metabolites of vicagrel and clopidogrel in human plasma

doi:10.1016/j.jpba.2017.11.019

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 上海药物代谢研究中心

	Development and validation of a sensitive and rapid UHPLC-MS/MS method for the simultaneous quantification of the common active and inactive metabolites of vicagrel and clopidogrel in human plasma
	Liu, Cai 3; Lu, Youming 3; Sun, Hongbin 4,5; Yang, Jin 1; Liu, Yongqiang 2; Lai, Xiaojuan 2; Gong, Yanchun 2; Liu, Xuefang 2; Li, Yongguo 6; Zhang, Yifan3
刊名	JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
	2018-02-05
卷号	149 页码:394-402
关键词	Vicagrel Clopidogrel Active metabolite LC-MS/MS Human plasma P2Y(12) inhibitor
ISSN号	0731-7085
DOI	10.1016/j.jpba.2017.11.019
文献子类	Article
英文摘要	Vicagrel, an analog of clopidogrel, is a novel thienopyridine P2Y(12) antagonist in clinical development in China for the treatment of acute coronary syndromes. Vicagrel and clopidogrel are prodrugs requiring metabolic activation to produce a pharmacologically active thiol metabolite (H4) in vivo. The formation of H4 from vicagrel in humans is promising more efficient and consistent than that from clopidogrel. After oral dosing of vicagrel or clopidogrel to humans, the active thiol metabolite H4 and two inactive metabolites closely related to H4 formation (the thiol metabolite H3 and the S-methylated metabolite SM3) were observed in plasma; SM3 was the most abundant drug-related component of vicagrel in circulation. In this study, a sensitive, rapid, and reliable UHPLC-MS/MS method was developed for the simultaneous determination of derivatized H3 (MP-H3), derivatized H4 (MP-H4), and SM3 in human plasma to investigate the pharmacokinetics of vicagrel in healthy subjects compared with clopidogrel. After extracted from 50 mu L of plasma by simple protein precipitation, the analytes and stable isotope-labeled internal standards were separated on an Acquity UPLC BEH C-18 column (100 mm x 2.1 mm, 1.7 mu m). The mobile phase was acetonitrile-water-formic acid (45:55:0.0275, v/v/v) delivered at a flow rate of 0.45 mL/min under isocratic elution. The total chromatographic run time was 6 min. MP-H3, MP-H4, and SM3 were separated from their corresponding isomers under the chromatographic conditions. Mass spectrometric detection was conducted in multiple reaction monitoring mode on an AB Sciex Qtrap 5500 System using a positive electrospray ionization interface. The calibration curves were linear in the following ranges: 0.100-200 ng/mL for MP-H3 and MP-H4 and 1.00-1000 ng/mL for SM3. The intra- and inter-day accuracy and precision for each analyte at all concentrations were within acceptable limits (+/- 15%). The validated method was successfully applied to compare the pharmacokinetics of vicagrel and clopidogrel after a single oral administration to healthy subjects in the first-in-human study of vicagrel. (C) 2017 Elsevier B.V. All rights reserved.
WOS关键词	THIOL METABOLITE ; PHARMACOKINETICS ; RESISTANCE ; ACID
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER SCIENCE BV
WOS记录号	WOS:000424315700050
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279913]
专题	上海药物代谢研究中心中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Zhong, Dafang
作者单位	1.China Pharmaceut Univ, Ctr Drug Metab & Pharmacokinet, Nanjing 210009, Jiangsu, Peoples R China; 2.Jiangsu Vcare PharmaTech Co Ltd, 15 Wanshou Rd, Nanjing 211800, Jiangsu, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 501 Haike Rd, Shanghai 201203, Peoples R China; 4.China Pharmaceut Univ, Coll Pharm, State Key Lab Nat Med, 24 Tongjia Xiang, Nanjing 210009, Jiangsu, Peoples R China; 5.China Pharmaceut Univ, Coll Pharm, Ctr Drug Discovery, 24 Tongjia Xiang, Nanjing 210009, Jiangsu, Peoples R China; 6.Hua Med Shanghai Ltd, 275 Ai Di Sheng Rd, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Liu, Cai,Lu, Youming,Sun, Hongbin,et al. Development and validation of a sensitive and rapid UHPLC-MS/MS method for the simultaneous quantification of the common active and inactive metabolites of vicagrel and clopidogrel in human plasma[J]. JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS,2018,149:394-402.
APA	Liu, Cai.,Lu, Youming.,Sun, Hongbin.,Yang, Jin.,Liu, Yongqiang.,...&Zhong, Dafang.(2018).Development and validation of a sensitive and rapid UHPLC-MS/MS method for the simultaneous quantification of the common active and inactive metabolites of vicagrel and clopidogrel in human plasma.JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS,149,394-402.
MLA	Liu, Cai,et al."Development and validation of a sensitive and rapid UHPLC-MS/MS method for the simultaneous quantification of the common active and inactive metabolites of vicagrel and clopidogrel in human plasma".JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS 149(2018):394-402.