盐酸丁咯地尔在人血浆和肝微粒体中代谢产物鉴定  

Identification of metabolites of buflomedil hydrochloride in human

作　　者：徐静静[1] 孙璐[1] 杨学欣 封晓欣 王侠[1] 

机构地区：[1]沈阳药科大学药学院,辽宁沈阳110016

出　　处：《沈阳药科大学学报》2017年第8期667-673,共7页Journal of Shenyang Pharmaceutical University

基　　金：辽宁省教育厅项目(L2014390);沈阳药科大学中青年教师中长期培养计划项目(ZQN2015007)

摘　　要：目的研究盐酸丁咯地尔在人体的代谢情况。方法采用UPLC-QTOF/MS法发现并鉴定盐酸丁咯地尔在人血浆和肝微粒体孵化体系中的代谢产物。采用HSS T3 C18色谱柱(100 mm×2.1 mm,1.8μm),以5 mmol·L^(-1)醋酸铵水溶液(含体积分数0.05%的甲酸)(A)-甲醇(B)为流动相梯度洗脱,流速为0.4 m L·min^(-1),采用ESI离子源,正离子模式下检测。结果通过与空白生物样品进行比较,在人血浆和肝微粒体中共发现了丁咯地尔及其24种代谢产物,其中18种为首次发现的代谢产物。根据代谢产物的色谱保留时间、准分子离子及碎片离子等信息,确定并推断了丁咯地尔及其代谢产物的结构,阐明了丁咯地尔在人体的代谢途径,包括去甲基化、氧化、羟基化、硫酸和葡萄糖醛酸结合途径。结论建立了UPLC-QTOF/MS方法研究了丁咯地尔在人体的代谢情况,为其化学结构类似药物和候选化合物的代谢研究提供依据。Objective To understand the metabolism of buflomedil hydrochloride in human. Methods An ultra performance liquid chromatography coupled with quanrupole time of flight mass spectrometry （ UPLC- QTOF/MS） was developed to identify the metabolites of buflomedil in human plasma and human liver microsomes. Chromatographic separation was performed on a HSS C18（ 100 mm×2.1 mm,1.8μm） column using gradient elution with mobile phase consisting of 5 mmol. L - 1 ammonium acetate containing 0. 1% （φ） formic acid （A） and acetonitrile containing 0. 1% （ φ） formic acid （ B ） at a flow rate of 0. 4 mL. rain - 1. A Micromass Q-TOF Premier mass spectrometer coupled to an electrospray ionization （ESI）source was operated in positive ion mode. Results A total of 24 metabolites were identified in human plasma and human liver microsomes by comparing the negative control samples, 18 of which were first discovered metabolites. According to the retention time, quasi-molecular ion and fragment ions, the structures of buflomedil and its metabolites were identified. The metabolism pathways in human were clarified, including demethylation, oxidation,hydroxylation, sulfation and glucuronide conjugation pathway. Conclusions The metabolic profile of buflomedil hydrochloride in human was established by UPLC-QTOF/MS, which provided useful information for the metabolic studies of the buflomedil structure similar drugs and candidate compounds.

关 键 词：盐酸丁咯地尔 人 血浆 肝微粒体 代谢产物鉴定 超高液相色谱串联四级杆飞行时间质谱 

分 类 号：R917[医药卫生—药物分析学]