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

34 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)1441-54
JournalMolecules
Volume13
Issue number7
DOIs
Publication statusPublished - 28 Jun 2008
MoE publication typeNot Eligible

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Floxuridine
transporter
Prodrugs
amino acids
drugs
Amino Acids
Growth
Oligopeptides
bioavailability
cells
affinity
Pharmaceutical Preparations
delivery
permeability
tumors
selectivity
Madin Darby Canine Kidney Cells
membranes
Cell growth
Drug delivery

Cite this

Tsume, Y., Vig, B. S., Sun, J., Landowski, C. P., Hilfinger, J. M., Ramachandran, C., & Amidon, G. L. (2008). Enhanced absorption and growth inhibition with amino acid monoester prodrugs of floxuridine by targeting hPEPT1 transporters. Molecules, 13(7), 1441-54. https://doi.org/10.3390/molecules13071441
Tsume, Yasuhiro ; Vig, Balvinder S. ; Sun, Jing ; Landowski, Christopher P. ; Hilfinger, John M. ; Ramachandran, Chandrasekharan ; Amidon, Gordon L. . / Enhanced absorption and growth inhibition with amino acid monoester prodrugs of floxuridine by targeting hPEPT1 transporters. In: Molecules. 2008 ; Vol. 13, No. 7. pp. 1441-54.
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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.",
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Tsume, Y, Vig, BS, Sun, J, Landowski, CP, Hilfinger, JM, Ramachandran, C & Amidon, GL 2008, 'Enhanced absorption and growth inhibition with amino acid monoester prodrugs of floxuridine by targeting hPEPT1 transporters', Molecules, vol. 13, no. 7, pp. 1441-54. https://doi.org/10.3390/molecules13071441

Enhanced absorption and growth inhibition with amino acid monoester prodrugs of floxuridine by targeting hPEPT1 transporters. / Tsume, Yasuhiro; Vig, Balvinder S.; Sun, Jing; Landowski, Christopher P. ; Hilfinger, John M.; Ramachandran, Chandrasekharan ; Amidon, Gordon L. .

In: Molecules, Vol. 13, No. 7, 28.06.2008, p. 1441-54.

Research output: Contribution to journalArticleScientificpeer-review

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AU - Tsume, Yasuhiro

AU - Vig, Balvinder S.

AU - Sun, Jing

AU - Landowski, Christopher P.

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AU - Ramachandran, Chandrasekharan

AU - Amidon, Gordon L.

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N2 - 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.

AB - 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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