Enhanced absorption and growth inhibition with amino acid monoester prodrugs of floxuridine by targeting hPEPT1 transporters.
Enhanced absorption and growth inhibition with amino acid monoester prodrugs of floxuridine by targeting hPEPT1 transporters.
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DOI：
10.3390/molecules13071441
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发表时间：
2008-06-28
期刊：
影响因子：
--
通讯作者：
Amidon GL
中科院分区：
文献类型：
--
作者：
Tsume Y;Vig BS;Sun J;Landowski CP;Hilfinger JM;Ramachandran C;Amidon GL
合成了一系列氟尿嘧啶核苷氨基酸单酯前药，并评价其口服生物利用度的提高以及通过寡肽转运蛋白靶向递送药物的可行性。所有氟尿苷 5'-氨基酸单酯前药均表现出 PEPT1 亲和力，在 Caco-2 细胞中 Gly-Sar 摄取抑制系数 (IC50) 范围为 0.7 – 2.3 mM，在 AsPC-1 细胞中为 2.0 – 4.8 mM，而氟尿苷的抑制系数分别为 7.3 mM 和 6.3 mM。氟尿苷前药 (1.01 – 5.31 x 10-6 cm/sec) 和氟尿苷 (0.48 x 10-6 cm/sec) 的 Caco-2 膜渗透性远高于 5-FU (0.038 x 10-6 cm/sec)。用人寡肽转运蛋白 PEPT1 (MDCK/hPEPT1) 稳定转染的 MDCK 细胞在前药存在下表现出增强的细胞生长抑制作用。这种前药策略提供了巨大的潜力，不仅可以增加药物吸收，还可以提高肿瘤选择性和药物疗效。
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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