Comparative pharmacokinetic study of PEGylated gemcitabine and gemcitabine in rats by LC-MS/MS coupled with pre-column derivatization and MS technique
AffiliationUniv Arizona, Coll Pharm
MetadataShow full item record
CitationYin, L., Ren, T., Zhao, S., Shi, M., & Gu, J. (2020). Comparative pharmacokinetic study of PEGylated gemcitabine and gemcitabine in rats by LC-MS/MS coupled with pre-column derivatization and MSALL technique. Talanta, 206, 120184.
Rights© 2019 Elsevier B.V. All rights reserved.
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at firstname.lastname@example.org.
AbstractGemcitabine is a small molecular antitumor compound used to treat many types of solid tumors. The clinical application of gemcitabine is limited by its short biological half-life, rapid metabolism and poor tumor tissue targeting. The covalent attachment of polyethylene glycol to gemcitabine is a promising technique to overcome these limitations. After PEGylation, PEGylated gemcitabine could be metabolized into gemcitabine and its metabolites in vivo. Due to the scale effect of PEGylated gemcitabine, the DMPK process of the original drug is greatly changed. Therefore, understanding the pharmacokinetic behavior of PEGylated gemcitabine, gemcitabine and the metabolite dFdU in vivo is really important to clarify the antitumoral activity of these compounds. It would also guide the development of other PEGylated drugs. Due to the complex structure and diverse physiochemical property of PEG, direct quantification analysis of PEGylated gemcitabine presented many challenges in terms of assay sensitivity, selectivity, and robustness. In this article, a data-independent acquisition method, MSALL-based approach using electrospray ionization (ESI) coupled quadrupole time of flight mass spectrometry (MS), was utilized for the determination of PEGylated gemcitabine in rat plasma. The technique consists of a Q1 mass window through all the precursor ions, fragmenting and recording all product ions. PEGylated gemcitabine underwent dissociation in collision cell to generate a series of PEG related ions at m/z 89.0604, 133.0868, 177.1129 of 2, 3, 4 repeating ethylene oxide subunits and PEGylated gemcitabine related ions at m/z 112.0514. PEGylated gemcitabine was detected by the high resolution extracted ions based on the specific compound. For gemcitabine and dFdU, the study used derivatization of these high polarity compounds with dansyl chloride to improve their chromatographic retention. This paper describes comparative pharmacokinetic study of PEGylated gemcitabine and gemcitabine in rats by LC-MS/MS coupled with pre-column derivatization and MSALL technique. The results show that PEGylation could reduce the drug clearance of the conjugated compounds and increase the drug plasma half-life. After administration of PEGylated gemcitabine, the exposure of the free gemcitabine in vivo is lower than administration of gemcitabine, which means that PEGylated gemcitabine possesses lower toxicity compared with gemcitabine.
Note24 month embargo; published online: 27 July 2019
VersionFinal accepted manuscript
SponsorsNational Natural Science Foundation of ChinaNational Natural Science Foundation of China [81703607, 81430087, 81603182, 81673396, 81872831, 81773692]; Jilin Province Science and Technoligy Development plan project [20190103082JH]; Science and Technology Major Specialized Projects for "significant new drugs creation" of the 12th five-year plan [2012ZX09303-015, 2014ZX09303303]; National Key Technology R&D Program of the Ministry of Science and TechnologyNational Key Technology R&D Program [2012BA130B00]; CERS-China Equipment and Education Resources System [CERS-1-70]
- MS<sup>All</sup> strategy for comprehensive quantitative analysis of PEGylated-doxorubicin, PEG and doxorubicin by LC-high resolution q-q-TOF mass spectrometry coupled with all window acquisition of all fragment ion spectra.
- Authors: Yin L, Su C, Ren T, Meng X, Shi M, Paul Fawcett J, Zhang M, Hu W, Gu J
- Issue date: 2017 Nov 6
- Simultaneous determination of gemcitabine prodrug, gemcitabine and its major metabolite 2', 2'-difluorodeoxyuridine in rat plasma by UFLC-MS/MS.
- Authors: Sun Y, Zhen L, Peng Y, Wang J, Fei F, Aa L, Jiang W, Pei X, Lu L, Liu J, Wang G, Hao K
- Issue date: 2018 May 1
- Development and Application of an MS<sup>ALL</sup>-Based Approach for the Quantitative Analysis of Linear Polyethylene Glycols in Rat Plasma by Liquid Chromatography Triple-Quadrupole/Time-of-Flight Mass Spectrometry.
- Authors: Zhou X, Meng X, Cheng L, Su C, Sun Y, Sun L, Tang Z, Fawcett JP, Yang Y, Gu J
- Issue date: 2017 May 16
- Determination of gemcitabine and its metabolite in extracellular fluid of rat brain tumor by ultra performance liquid chromatography-tandem mass spectrometry using microdialysis sampling after intralesional chemotherapy.
- Authors: Sun Y, Tang D, Chen H, Zhang F, Fan B, Zhang B, Fang S, Lu Q, Wei Y, Yin J, Yin X
- Issue date: 2013 Mar 1
- Development of a sensitive and selective LC-MS/MS method for simultaneous determination of gemcitabine and 2,2-difluoro-2-deoxyuridine in human plasma.
- Authors: Bowen C, Wang S, Licea-Perez H
- Issue date: 2009 Jul 15