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

doi:10.3390/molecules13071441

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

Not published at VTT

Research output: Contribution to journal › Article › Scientific › peer-review

38 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 language	English
Pages (from-to)	1441-54
Number of pages	14
Journal	Molecules
Volume	13
Issue number	7
DOIs	https://doi.org/10.3390/molecules13071441
Publication status	Published - 28 Jun 2008
MoE publication type	A1 Journal article-refereed

Keywords

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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10.3390/molecules13071441

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title = "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.",

keywords = "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",

author = "Yasuhiro Tsume and Vig, {Balvinder S.} and Jing Sun and Landowski, {Christopher P.} and Hilfinger, {John M.} and Chandrasekharan Ramachandran and Amidon, {Gordon L.}",

year = "2008",

month = jun,

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doi = "10.3390/molecules13071441",

language = "English",

volume = "13",

pages = "1441--54",

journal = "Molecules",

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publisher = "MDPI",

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T1 - Enhanced absorption and growth inhibition with amino acid monoester prodrugs of floxuridine by targeting hPEPT1 transporters

AU - Tsume, Yasuhiro

AU - Vig, Balvinder S.

AU - Sun, Jing

AU - Landowski, Christopher P.

AU - Hilfinger, John M.

AU - Ramachandran, Chandrasekharan

AU - Amidon, Gordon L.

PY - 2008/6/28

Y1 - 2008/6/28

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.

KW - Absorption/drug effects

KW - Amino Acids/chemical synthesis

KW - Animals

KW - Antimetabolites, Antineoplastic/chemical synthesis

KW - Caco-2 Cells

KW - Cell Proliferation/drug effects

KW - Dogs

KW - Drug Delivery Systems

KW - Esters

KW - Floxuridine/pharmacokinetics

KW - Growth Inhibitors/pharmacokinetics

KW - Humans

KW - Peptide Transporter 1

KW - Prodrugs/chemical synthesis

KW - Symporters/biosynthesis

U2 - 10.3390/molecules13071441

DO - 10.3390/molecules13071441

M3 - Article

C2 - 18719516

SN - 1420-3049

VL - 13

SP - 1441

EP - 1454

JO - Molecules

JF - Molecules

IS - 7

ER -

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

Abstract

Keywords

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