Pharmaceutical Research

, Volume 22, Issue 9, pp 1510–1518 | Cite as

Floxuridine Amino Acid Ester Prodrugs: Enhancing Caco-2 Permeability and Resistance to Glycosidic Bond Metabolism

  • Christopher P. Landowski
  • Xueqin Song
  • Philip L. Lorenzi
  • John M. Hilfinger
  • Gordon L. Amidon
Research Paper



The aim of this study was to synthesize amino acid ester prodrugs of 5-fluoro-2′-deoxyuridine (floxuridine) to enhance intestinal absorption and resistance to glycosidic bond metabolism.


Amino acid ester prodrugs were synthesized and examined for their hydrolytic stability in human plasma, in Caco-2 cell homogenates, and in the presence of thymidine phosphorylase. Glycyl-l-sarcosine uptake inhibition and direct uptake studies with HeLa/PEPT1 cells [HeLa cells overexpressing oligopeptide transporter (PEPT1)] were conducted to determine PEPT1-mediated transport and compared with permeability of the prodrugs across Caco-2 monolayers.


Isoleucyl prodrugs exhibited the highest chemical and enzymatic stability. The prodrugs enhanced the stability of the glycosidic bond of floxuridine. Thymidine phosphorylase rapidly cleaved floxuridine to 5-fluorouracil, whereas with the prodrugs no detectable glycosidic bond cleavage was observed. The 5′-l-isoleucyl and 5′-l-valyl monoester prodrugs exhibited 8- and 19-fold PEPT1-mediated uptake enhancement in HeLa/PEPT1 cells, respectively. Uptake enhancement in HeLa/PEPT1 cells correlated highly with Caco-2 permeability for all prodrugs tested. Caco-2 permeability of 5′-l-isoleucyl and 5′-l-valyl prodrugs was 8- to 11-fold greater compared with floxuridine.


Amino acid ester prodrugs such as isoleucyl floxuridine that exhibit enhanced Caco-2 transport and slower rate of enzymatic activation to parent, and that are highly resistant to metabolism by thymidine phosphorylase may improve oral delivery and therapeutic index of floxuridine.

Key Words

Caco-2 permeability floxuridine prodrugs metabolism PEPT1 thymidine phosphorylase 



HeLa cells overexpressing PEPT1


oligopeptide transporter



This work was supported by grant NIGMD-1R01GM 37188.


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Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Christopher P. Landowski
    • 1
  • Xueqin Song
    • 1
  • Philip L. Lorenzi
    • 1
  • John M. Hilfinger
    • 2
  • Gordon L. Amidon
    • 1
  1. 1.Department of Pharmaceutical Sciences, College of PharmacyUniversity of MichiganAnn ArborUSA
  2. 2.TSRL, Inc.Ann ArborUSA

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