Enhanced absorption and growth inhibition with amino acid monoester prodrugs of floxuridine by targeting hPEPT1 transporters.

Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry
Yasuhiro TsumeGordon L Amidon

Abstract

A series of amino acid monoester prodrugs of floxuridine was synthesized and evaluated for the improvement of oral bioavailability and the feasibility of target drug delivery via oligopeptide transporters. All floxuridine 5'-amino acid monoester prodrugs exhibited PEPT1 affinity, with inhibition coefficients of Gly-Sar uptake (IC50) ranging from 0.7 - 2.3 mM in Caco-2 and 2.0 - 4.8 mM in AsPC-1 cells, while that of floxuridine was 7.3 mM and 6.3 mM, respectively. Caco-2 membrane permeabilities of floxuridine prodrugs (1.01 - 5.31 x 10(-6 )cm/sec) and floxuridine (0.48 x 10(-6 )cm/sec) were much higher than that of 5-FU (0.038 x 10(-6) cm/sec). MDCK cells stably transfected with the human oligopeptide transporter PEPT1 (MDCK/hPEPT1) exhibited enhanced cell growth inhibition in the presence of the prodrugs. This prodrug strategy offers great potential, not only for increased drug absorption but also for improved tumor selectivity and drug efficacy.

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Citations

Jan 24, 2012·ACS Combinatorial Science·Lihui ZhangYuhong Xu
Dec 25, 2012·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Bei Yang, David E Smith
Mar 28, 2012·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Yasuhiro Tsume, Gordon L Amidon
Apr 27, 2013·Future Medicinal Chemistry·Ahmed KhalilWerner Tjarks
Nov 22, 2011·Future Medicinal Chemistry·Donna A Volpe
Oct 16, 2014·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Arik DahanShimon Ben-Shabat
Jun 13, 2009·Expert Opinion on Drug Metabolism & Toxicology·Matthias Brandsch
Apr 9, 2013·Pharmacological Reports : PR·Jolanta B ZawilskaAgnieszka B Olejniczak
Apr 1, 2011·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Yasuhiro TsumeGordon L Amidon
Mar 21, 2016·European Journal of Medicinal Chemistry·Agnieszka Szymańska-MichalakAdam Kraszewski
Nov 26, 2009·Chemistry & Biodiversity·Christa E Müller
Oct 24, 2013·Biopharmaceutics & Drug Disposition·Han-Joo MaengWon-Sik Shim
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Dec 24, 2013·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Yasuhiro TsumeGordon L Amidon
Apr 1, 2014·Drug Discovery Today·Fatima el BahhajPhilippe Bertrand
Jun 21, 2016·Journal of Pharmaceutical Sciences·Teruo Murakami
Jun 14, 2016·Expert Opinion on Drug Delivery·Amit K Jain, Sanyog Jain
Aug 11, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Yasuhiro TsumeGordon L Amidon

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Methods Mentioned

BETA
NMR
Assay
column chromatography
nuclear magnetic resonance
Protein Assay

Software Mentioned

Waters Millennium ® 32
GraphPad Prism

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