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Molecules 2008, 13(7), 1441-1454; doi:10.3390/molecules13071441

Enhanced Absorption and Growth Inhibition with Amino Acid Monoester Prodrugs of Floxuridine by Targeting hPEPT1 Transporters

1
Department of Pharmaceutical Science, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109-1065, USA
2
Pharmaceutical Research Institute, Bristol-Myers Squibb Company, New Brunswick, NJ 08502, USA
3
Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA
4
Institute of Biochemistry and Molecular Medicine, University of Bern, CH-3012 Bern, Switzerland
5
TSRL, Inc. Ann Arbor, Michigan 48108, USA
*
Author to whom correspondence should be addressed.
Received: 12 June 2008 / Accepted: 27 June 2008 / Published: 28 June 2008
(This article belongs to the Special Issue 5-Fluorouracil)
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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.
Keywords: 5-FU; floxuridine; prodrugs; Caco-2 permeability; cell proliferation assays; oligopeptide transporter 1 (PEPT1) 5-FU; floxuridine; prodrugs; Caco-2 permeability; cell proliferation assays; oligopeptide transporter 1 (PEPT1)
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Tsume, Y.; Vig, B.S.; Sun, J.; Landowski, C.P.; Hilfinger, J.M.; Ramachandran, C.; Amidon, G.L. Enhanced Absorption and Growth Inhibition with Amino Acid Monoester Prodrugs of Floxuridine by Targeting hPEPT1 Transporters. Molecules 2008, 13, 1441-1454.

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