广东药科大学学报2025，Vol.41Issue(3)：36-43,8.DOI:10.16809/j.cnki.2096-3653.2025011402
基于DMPK优化的金合欢素水溶性前药的合成及其生物利用度研究
DMPK-based prodrug strategy and oral bioavailability studies toward multiple atrial-specific potassium ion channels inhibitor acacetin
摘要
Abstract
Objective To design and synthesize a series of acacetin(Aca)prodrugs(ACTN001-ACTN005).Methods The equilibrium solubility(in water,simulated intestinal fluid[SIF],and simulated gastric fluid[SGF])and oil-water partition coefficients(Log P)of five Aca prodrugs were evaluated.ACTN001 and ACTN005 were selected for further investigation of their in vitro conversion profiles in rat,rabbit,and human plasma,as well as their pharmacokinetic parameters and oral bioavailability in rats.Results ACTN001 exhibited equilibrium solubility>9 μg/mL in all three media,representing a 100-fold increase over the parent drug.ACTN005 demonstrated solubilities of 1 151.2 μg/mL in water and 15.5 μg/mL in SIF,corresponding to 16 666-and 166-fold improvements,respectively.In vitro,ACTN001 failed to convert to Aca in rat,rabbit,or human plasma,whereas ACTN005 converted to Aca only in rat plasma.Both prodrugs underwent in vivo conversion to Aca in rats,with ACTN005 showing a higher absorption rate constant(0.029 h-1 vs.0.013 h-1 for ACTN001).The absolute bioavailability of ACTN001 and ACTN005 reached 5.57%and 17.1%,respectively,reflecting 5-and 15-fold enhancements compared to native Aca.Conclusion ACTN001 and ACTN005 significantly improved the aqueous solubility and oral bioavailability of Aca.关键词
金合欢素/前药/溶解度/体外代谢/生物利用度Key words
acacetin/prodrug/solubility/in vitro bioconversion/bioavailability分类
药学引用本文复制引用
丁舒舒,丁秋雨,陈倩,史莹莹,张涛,王亚晶,黄险峰..基于DMPK优化的金合欢素水溶性前药的合成及其生物利用度研究[J].广东药科大学学报,2025,41(3):36-43,8.基金项目
国家自然科学基金青年项目(81803471) （81803471）
