Design of Fexofenadine Prodrugs Based on Tissue-Specific Esterase Activity and Their Dissimilar Recognition by P-Glycoprotein.
Design of Fexofenadine Prodrugs Based on Tissue-Specific Esterase Activity and Their Dissimilar Recognition by P-Glycoprotein.
复制标题
基于组织特异性酯酶活性及其 P-糖蛋白不同识别的非索非那定前药设计。
DOI：
10.1002/jps.24467
复制
发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Imai T.
中科院分区：
文献类型：
--
作者：
Ohura K;Nakada Y;Kotani S;Imai T.
本研究的目的是为非索非那定（FXD）开发一种合适的前药，FXD是一种模型母体药物，对肠酯酶具有抗性，但可通过肝酯酶转化为FXD。羧酸酯酶（Carboxylesterases，CES），即人羧酸酯酶1（human carboxylesterase 1，hCE 1）和人羧酸酯酶2（human carboxylesterase 2，hCE 2），分别是人体肝脏和肠道中的主要酯酶。这两种CES显示出完全不同的底物特异性，尤其是hCE 2对具有大酰基的前药的水解较差。FXD含有羧基，由于膜渗透性低和P-糖蛋白（P-gp）外排，吸收较差。因此，通过取代FXD中的羧基，合成了两种潜在的FXD前药，乙基-FXD和2-羟乙基-FXD。这两种衍生物都耐肠水解，表明它们作为完整的前药被吸收。乙基-FXD被肝hCE 1水解，但2-羟乙基-FXD不被水解。两种衍生物在人P-gp阴性LLC-PK 1细胞中均显示出高膜渗透性。在过表达人P-gp的LLC-GA 5-COL 300细胞中，乙基-FXD由P-gp转运，但其外排容易饱和。而2-羟乙基-FXD显示出比FXD更有效的P-gp介导的转运。尽管2-羟乙基-FXD的结构仅通过羟基取代而不同于乙基-FXD，但2-羟乙基-FXD不适合作为前药。然而，乙基-FXD是一个很好的候选前药，因为良好的肠吸收和hCE 1的肝转化。© 2015 Wiley Periodicals，Inc.和American Pharmacologist Association J Pharm Sci 104：3076-3083，2015
The aim of this study was to develop a suitable prodrug for fexofenadine (FXD), a model parent drug, that is resistant to intestinal esterase but converted to FXD by hepatic esterase. Carboxylesterases (CESs), human carboxylesterase 1 (hCE1) and human carboxylesterase 2 (hCE2), are the major esterases in human liver and intestine, respectively. These two CESs show quite different substrate specificities, and especially, hCE2 poorly hydrolyzes prodrugs with large acyl groups. FXD contains a carboxyl group and is poorly absorbed because of low membrane permeability and efflux by P-glycoprotein (P-gp). Therefore, two potential FXD prodrugs, ethyl-FXD and 2-hydroxyethyl-FXD, were synthesized by substitution of the carboxyl group in FXD. Both derivatives were resistant to intestinal hydrolysis, indicating their absorption as intact prodrugs. Ethyl-FXD was hydrolyzed by hepatic hCE1, but 2-hydroxyethyl-FXD was not. Both derivatives showed high membrane permeability in human P-gp-negative LLC-PK1 cells. In LLC-GA5-COL300 cells overexpressing human P-gp, ethyl-FXD was transported by P-gp, but its efflux was easily saturated. Whereas 2-hydroxyethyl-FXD showed more efficient P-gp-mediated transport than FXD. Although the structure of 2-hydroxyethyl-FXD only differs from ethyl-FXD by substitution of a hydroxyl group, 2-hydroxyethyl-FXD is unsuitable as a prodrug. However, ethyl-FXD is a good candidate prodrug because of good intestinal absorption and hepatic conversion by hCE1. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3076–3083, 2015