D-氨基葡萄糖修饰的5-氟尿嘧啶衍生物在动物体内靶向性研究

发布时间：2019-06-24 11:25

【摘要】：目的合成5-氟尿嘧啶-D-氨基葡萄糖衍生物,初步考察衍生物在小鼠体内的分布情况。方法以酰胺键为连接键制备5-氟尿嘧啶-D-氨基葡萄糖衍生物,建立5-氟尿嘧啶及其衍生物体内外高效液相色谱(HPLC)分析方法;考察5-氟尿嘧啶及其衍生物在缓冲液和生物样品液中的体外稳定性;通过HPLC法测定原药及其衍生物在小鼠体内各组织分布情况,对衍生物进行靶向性评价。结果~1H-NMR、~(13)C-NMR和LC-MS均证实了目标化合物的成功合成;在pH7.4缓冲液、血浆和肾匀浆液中,衍生物的稳定性均很好,几乎不发生降解(10%);小鼠尾静脉注射给药后,5-氟尿嘧啶-D-氨基葡萄糖衍生物分布到肾的AUC_(0-t)为(9680.07±330.20)μg·g~(-1)·min,较原药提高了20.3倍,其相对摄取率(RE值)为21.27,峰浓度比(CE值)为10.45。此外,衍生物血浆中的分布亦明显增加,且消除时间延长。结论经D-氨基葡萄糖修饰的5-氟尿嘧啶衍生物体外稳定性良好,体内分布具有明显的肾靶向性。
[Abstract]:Objective To study the distribution of 5-fluorouridine-D-amino glucose derivative in mice. Methods 5-fluorouridine-D-amino-glucose derivatives were prepared by using the melamine bond as the connecting key to establish the method of high performance liquid chromatography (HPLC) of 5-fluorouridine-D-amino glucose derivatives. The in vitro stability of 5-fluorouramide and its derivatives in buffer and biological sample was investigated. The distribution of the drug and its derivatives in the mice was determined by HPLC. Results ~ 1H-NMR, ~ (13) C-NMR and LC-MS both confirmed the successful synthesis of the target compound; in the pH 7.4 buffer, plasma and kidney homogenate, the stability of the derivative was good, and no degradation was observed (10%); after the injection of the tail vein of the mouse, The AUC _ (0-t) of 5-fluorouridine-D-amino-glucose derivative in the kidney was (0.07-330.20). mu. g 路 g-(-1) 路 min, and the relative intake rate (RE value) was 21.27, and the peak-to-peak concentration ratio (CE value) was 10.45. In addition, the distribution of the derivative plasma is also significantly increased and the elimination time is prolonged. Conclusion The 5-fluorouramide derivatives modified by D-aminoglucose have good in vitro stability, and the in vivo distribution has obvious renal targeting.
【作者单位】：四川大学华西药学院;重庆市妇幼保健院;
【分类号】：R965

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