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.

Autor: Liu C; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China., Lu Y; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China., Sun H; State Key Laboratory of Natural Medicines and Center of Drug Discovery, College of Pharmacy, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China., Yang J; Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China., Liu Y; Jiangsu Vcare PharmaTech Co. Ltd., 15 Wanshou Road, Nanjing 211800, China., Lai X; Jiangsu Vcare PharmaTech Co. Ltd., 15 Wanshou Road, Nanjing 211800, China., Gong Y; Jiangsu Vcare PharmaTech Co. Ltd., 15 Wanshou Road, Nanjing 211800, China., Liu X; Jiangsu Vcare PharmaTech Co. Ltd., 15 Wanshou Road, Nanjing 211800, China., Li Y; Hua Medicine (Shanghai) Ltd., 275 Ai Di Sheng Road, Shanghai 201203, China., Zhang Y; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China., Chen X; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China., Zhong D; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China. Electronic address: dfzhong@simm.ac.cn.
Jazyk: angličtina
Zdroj: Journal of pharmaceutical and biomedical analysis [J Pharm Biomed Anal] 2018 Feb 05; Vol. 149, pp. 394-402. Date of Electronic Publication: 2017 Nov 06.
DOI: 10.1016/j.jpba.2017.11.019
Abstrakt: 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 50μL of plasma by simple protein precipitation, the analytes and stable isotope-labeled internal standards were separated on an Acquity UPLC BEH C 18 column (100mm×2.1mm, 1.7μm). The mobile phase was acetonitrile-water-formic acid (45:55:0.0275, v/v/v) delivered at a flow rate of 0.45mL/min under isocratic elution. The total chromatographic run time was 6min. 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: 0.100-200ng/mL for MP-H3 and MP-H4 and 1.00-1000ng/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.
(Copyright © 2017 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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