肼屈嗪-N-乳糖结合物的制备以及体外代谢研究

Synthesis of hydralazine-N-lactose and its metabolites in vitro

肼屈嗪-N-乳糖结合物是盐酸肼屈嗪片剂中主要杂质。以肼屈嗪和乳糖为原料,使用硅胶柱与十八烷基硅烷键合硅胶填料的制备柱制备并纯化了肼屈嗪-N-乳糖结合物,并对其在SD大鼠体外中的代谢物进行鉴定。利用LC-MS/MS对代谢物进行结构鉴定,与空白样品进行对比。肼屈嗪-N-乳糖结合物在经过体外代谢后,产生1,2,4-三唑并[3,4-a]酞嗪,3-甲基-1,2,4-三唑并[3,4-a]酞嗪,3-(1-羟基)乙基-1,2,4-三唑并[3,4-a]酞嗪,3-羟甲基-1,2,4-三唑并[3,4-a]酞嗪,肼屈嗪和脱氢肼屈嗪-N-乳糖结合物等6种主要代谢产物。本研究对肼屈嗪与乳糖的结合物转化以及肼屈嗪制剂的杂质安全性研究具有参考意义。

Hydralazine-N-lactose is a main impurity in hydralazine tablets.Hydralazine and lactose were used as raw materials,and silica gel column and preparation column of octadecylsilane bonded silica were selected to prepare and purify hydralazine-N-lactose.Its in vitro metabolites were identified by utilizing SD rat liver microsomes.The results of samples in vitro were compared with blank group and the resulting metabolites structures were identified by LC-MS/MS.Hydrazine-N-lactose produced six main metabolites,including s-triazolo [3,4-a ]phthalazine,3-methyl-s-triazolo [ 3,4-a ] phthalazine,3-（1-hydroxy） methyl-s-triazolo [ 3,4-a ] phthalazine,3-hydroxymethyl-s-triazolo[3,4-a]phthalazine,hydralazine and dehydro-hydralazine-N-lactose after in vitro metabolism.This study will be valuable in hydralazine-lactose conjunctions metabolism research and hydralazine formulation safety.