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

Yasuhiro Tsume, Balvinder S. Vig, Jing Sun, Christopher P. Landowski, John M. Hilfinger, Chandrasekharan Ramachandran, Gordon L. Amidon

Research output: Contribution to journalArticleScientificpeer-review

35 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)1441-54
Number of pages14
Issue number7
Publication statusPublished - 28 Jun 2008
MoE publication typeA1 Journal article-refereed



  • Absorption/drug effects
  • Amino Acids/chemical synthesis
  • Animals
  • Antimetabolites, Antineoplastic/chemical synthesis
  • Caco-2 Cells
  • Cell Proliferation/drug effects
  • Dogs
  • Drug Delivery Systems
  • Esters
  • Floxuridine/pharmacokinetics
  • Growth Inhibitors/pharmacokinetics
  • Humans
  • Peptide Transporter 1
  • Prodrugs/chemical synthesis
  • Symporters/biosynthesis

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