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    Comparative pharmacokinetic study of PEGylated gemcitabine and gemcitabine in rats by LC-MS/MS coupled with pre-column derivatization and MS technique

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    Name:
    TAL-S-19-02287.pdf
    Embargo:
    2021-07-27
    Size:
    731.1Kb
    Format:
    PDF
    Description:
    Final Accepted Manuscript
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    Author
    Yin, Lei
    Ren, Tianming
    Zhao, Shiying
    Shi, Meiyun
    Gu, Jingkai
    Affiliation
    Univ Arizona, Coll Pharm
    Issue Date
    2020-01-01
    Keywords
    Gemcitabine
    LC-MS/MS
    MS(ALL)
    PEGylated gemcitabine
    Pharmacokinetic
    
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    ELSEVIER
    Citation
    Yin, 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.
    Journal
    TALANTA
    Rights
    © 2019 Elsevier B.V. All rights reserved.
    Collection Information
    This 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 repository@u.library.arizona.edu.
    Abstract
    Gemcitabine 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.
    Note
    24 month embargo; published online: 27 July 2019
    ISSN
    0039-9140
    PubMed ID
    31514844
    DOI
    10.1016/j.talanta.2019.120184
    Version
    Final accepted manuscript
    Sponsors
    National 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]
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.talanta.2019.120184
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