氯硝柳胺丙戊酸酯的体外化学稳定性及体内药代动力学初步研究

Preliminary research on chemical stability of niclosamide-valproic acid ester and its pharmacokinetics in rat plasma

目的对具有潜在的组蛋白去乙酰化酶和蛋白酪氨酸激酶双重抑制作用的抗肿瘤化合物氯硝柳胺丙戊酸酯进行体外水解动力学、血浆稳定性及体内药代动力学初步研究。方法采用HPLC法研究体外氯硝柳胺丙戊酸酯在不同pH值的水溶液、血浆中的稳定性,以及体内研究大鼠静脉注射10 mg·kg-1氯硝柳胺丙戊酸酯后,测定不同时间点大鼠血浆中的氯硝柳胺丙戊酸酯及氯硝柳胺的浓度,对其血药浓度-时间采用BABP 3.0软件拟合,估算其药动学参数。结果血浆中氯硝柳胺丙戊酸酯、氯硝柳胺在血浆中0.1-100.0 mg·L-1范围内线性关系良好(r=0.9999),回收率>80%和日内及日间精密度<10%;氯硝柳胺丙戊酸酯体外在酸性及中性水溶液中比较稳定,在碱性水溶液中易水解,在体外血浆中水解半衰期为8.5 min;氯硝柳胺丙戊酸酯以10mg·kg-1静脉给药后,氯硝柳胺丙戊酸酯在大鼠体内的T12为(14.25±2.43)min,AUC0-t为(280.6±39.7)min·mg·L-1,氯硝柳胺在大鼠体内的T12为(1.61±0.32)min,AUC0-t为(57.1±20.4)min·mg·L-1。结论氯硝柳胺丙戊酸酯在体外具有一定的稳定性,同时体内能够水解成氯硝柳胺和丙戊酸。

Aim To investigate the chemical stability in vitro and its pharmacokinetics of niclosamide-valpro- ester （NVE） in rats in vivo. Method A HPLC method was used to study the hydrolysis of NVE in aqueous solutions of different pH values and the sta-bility in rat plasma in vitro, and to determinate the plasma concentration of NVE and niclosamide in rat plasma in vivo. After iv administration of NVE in rats at a dose of 10 mg·kg^-1, the plasma concentration of NVE and niclosamide were determined and the pharmacokinetic parameters were calculated by BABP 3.0. Result Calibration curves of NVE and niclosamide in rat plasma were linear over the range of 0. 1 - 100. 0 mg ·kg^-1. The extraction recoveries were higher than 80%. The intra- and inter-day precision （RSD%） were lower than 10%. NVE was relatively stable in acid and neutral aqueous solution, but easily hydro- lyzed in alkaline aqueous solution. The half-life of hy- drolysis in vitro plasma was 8.5 min. After iv adminis- tration of NVE in rats at a dose of 10 mg·kg^-1 , the T1/2 of NVE was （ 14.25 ±2.43 ） min and the AUC0-6 of NVEwas （280.6-39.7） min·kg^-1. The T1/ 2 of niclosamide was （ 1.61±0.32） min, and the AUCo_t of nielosamide was （57.1 ±20. 4） min · mg · L-1. Conclusion NVE has a certain stability in vitro, and at the same time, NVE could be hydrolyzed into nielosamide and valproie acid in vivo.