糖基修饰用于改善金合欢素口服吸收的考察

Investigation on Improvement of Oral Absorption of Acacetin by Glycosylated Modification

金合欢素(1)是一种选择性高、体内外抗房颤活性良好的黄酮化合物,但水溶性差和半衰期短的缺陷严重限制了其成药。为改善其水溶性、增强口服吸收率,该研究以肠道上的钠-葡萄糖转运蛋白1(SGLT1)为靶点,设计并合成了2个1糖苷前药。Caco-2细胞转运试验结果表明,1糖苷前药的渗透率均比1有显著提高,其转运由SGLT1介导,且受到多药耐药蛋白的外排作用。大鼠药动学研究结果显示,1的单糖前药和二糖前药的c_(max)值分别比1提高5和30倍,AUC相比1分别提升10和100倍,半衰期均延长2 h左右。以上研究结果表明,使用糖基修饰1可有效增强其口服吸收效率。

Acacetin(1)is a natural flavone that can prevent atrial fibrillation in vivo and in vitro with high specificity.However,low solubility and short half-life severely of 1 limit its medicinal application.In order to improve its water solubility and enhance oral absorption,two 1 glycosyl prodrugs targeting the intestinal sodium-glucose transporter1(SGLT1)were designed and synthesized.The results of Caco-2 cell transport experiment showed that the permeabilities of the two 1 glycosyl prodrugs were higher than 1.The permeability of the glycosyl prodrug was mediated by SGLT1 and was affected by the efflux of multi-drug resistant proteins.The pharmacokinetics results in rats showed that the c_(max)values of monosaccharide and disaccharide derivatives of 1 were 5 and 30 times higher than that of 1,respectively.The AUC values of them was 10 and 100 times higher than that of 1,respectively,and the half-lives of both derivatives were extended for about 2 hours.These results indicated that glycosyl modification of 1 could effectively enhance its oral absorption.