生物利用度
大豆黄酮
前药
化学
溶解度
氨基甲酸酯
药代动力学
亲脂性
色谱法
新陈代谢
有机化学
药理学
生物化学
染料木素
生物
内分泌学
作者
Yingchao Li,Xiaoyu Liu,Farong Lu,H.B. Li,Jiaming Zhang,Yawei Zhang,Wenchao Li,Weiping Wang,Miaomiao Yang,Zhining Ma,Hui Zhang,Xiaomian Zhou,Youjun Xu,Zhonggui He,Jin Sun,Tianhong Zhang,Qikun Jiang
标识
DOI:10.1021/acs.jafc.4c01251
摘要
Daidzein (DAN) is an isoflavone, and it is often found in its natural form in soybean and food supplements. DAN has poor bioavailability owing to its extremely low water solubility and first-pass metabolism. Herein, we hypothesized that a bioactivatable natural amino acid-bearing carbamate prodrug strategy could increase the water solubility and metabolic stability of DAN. To test our hypothesis, nine amino acid prodrugs of DAN were designed and synthesized. Compared with DAN, the optimal prodrug (daidzein-4′-O-CO-N-isoleucine, D-4′-I) demonstrated enhanced water solubility and improved phase II metabolic stability and activation to DAN in plasma. In addition, unlike the passive transport of DAN, D-4′-I maintained high permeability via organic anion-transporting polypeptide 2B1 (OATP2B1)-mediated transport. Importantly, D-4′-I increased the oral bioavailability by 15.5-fold, reduced the gender difference, and extended the linear absorption capacity in the pharmacokinetics of DAN in rats. Furthermore, D-4′-I exhibited dose-dependent protection against liver injury. Thus, the natural amino acid-bearing carbamate prodrug strategy shows potential in increasing water solubility and improving phase II metabolic stability to enhance the oral bioavailability of DAN.
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