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

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.

• Authors: Yasuhiro Tsume, Balvinder S Vig, Jing Sun, Christopher P Landowski, John M Hilfinger, Chandrasekharan Ramachandran, Gordon L Amidon
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 13 Issue 7 Pg. 1441-54 (Jun 28 2008) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 18719516 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Amino Acids
• Antimetabolites, Antineoplastic
• Esters
• Growth Inhibitors
• Peptide Transporter 1
• Prodrugs
• SLC15A1 protein, human
• Symporters
• Floxuridine

Topics

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