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

被引：39

作者：

Tsume, Yasuhiro ^{[1
]}

Vig, Balvinder S. ^{[2
]}

Sun, Jing ^{[3
]}

Landowski, Christopher P. ^{[4
]}

Hilfinger, John M. ^{[5
]}

Ramachandran, Chandrasekharan ^{[1
]}

Amidon, Gordon L. ^{[1
]}

机构：

[1] Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, Ann Arbor, MI 48109 USA

[2] Bristol Myers Squibb Co, Pharmaceut Res Inst, New Brunswick, NJ 08502 USA

[3] Univ Michigan, Dept Med Chem, Ann Arbor, MI 48109 USA

[4] Univ Bern, Inst Biochem & Mol Med, Inst Biochem & Mol Med, CH-3012 Bern, Switzerland

[5] TSRL Inc, Ann Arbor, MI 48108 USA

来源：

MOLECULES | 2008年 / 13卷 / 07期

关键词：

5-FU; floxuridine; prodrugs; Caco-2; permeability; cell proliferation assays; oligopeptide transporter 1 (PEPT1);

D O I：

10.3390/molecules13071441

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1441 / 1454

页数：14

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