摘要
目的:建立大鼠体外肝、肾和肺组织匀浆代谢评价模型,检测新型黄体生成素释放激素拮抗剂十肽(代号609)在3种模型中的代谢稳定性和代谢产物。方法:采用体外温孵的方法,通过液相色谱-质谱技术综合分析代谢产物与原型药物的质谱图和色谱图,鉴定其在大鼠肝匀浆中的酶解位点、代谢产物及代谢反应途径。结果:609在大鼠各组织匀浆中代谢速度是肝>肾>肺,代谢半衰期分别为8,54,70 min;主要的酶解位点在3位和4位以及4位和5位氨基酸之间,发生的代谢反应主要有氨基酸侧链的羟基脱水、脱烷基和甲基化。结论:本研究建立的3种组织匀浆模型适合用于肽类药物的早期代谢评价,所阐明的代谢位点和代谢途径可为该类化合物的结构优化提供实验依据。
Objective： To establish the rat liver, kidney and lung tissue homogenate models for evaluating the in vitro stability and metabolites of the novel luteinizing hormone releasing hormone （LHRH） antagonist （609）. Methods： The decapeptide 609 was incubated with rat tissue homogenates in vitro, and then the stability, proteolytic cleavage sites, metabolites and metabolic reactions were analyzed by high performance liquid chromatog- raphy-tandem mass spectrometry method. Results： The rank order of the degradation rate of 609 in the three ho- mogenates was liver 〉 kidney 〉 lung. The half-lives were 8, 54 and 70 min, respectively. 609 was first cleaved by an endopeptidase at three proteolytic cleavage sites located between 3rd and 4th, 4th and 5th amino acid sites. The further metabolic reactions included the dehydration, methylation and isopropyl dealkylation. Conclusions： Three tissue homogenate models are suitable for metabolic stability evaluation of peptide, and the results of metabolic mechanism will provide research ways for optimizing structure of peptides.
出处
《中国新药杂志》
CAS
CSCD
北大核心
2013年第16期1901-1906,共6页
Chinese Journal of New Drugs
基金
首都医科大学燕京医学院科研启动基金(13QD011)
关键词
十肽
稳定性
代谢物
液相色谱-串联质谱
decapeptide
stability
metabolites
high performance liquid chromatography-tandem mass spectrometry
