蛇葡萄素在大鼠肝微粒体中的代谢动力学及药用辅料对其抑制作用的研究

Study on Metabolic Kinetics of Ampelopsin in Rat Liver Microsomes and Its Inhibition Effect by Pharmaceutical Excipients

关键词:  蛇葡萄素  药用辅料  代谢动力学  代谢抑制

Key words:  ampelopsin  pharmaceutical excipients  metabolic kinetics  metabolic inhibition

摘要:

目的 研究蛇葡萄素在大鼠肝微粒体的代谢规律及药用辅料对其代谢的影响。方法 建立UPLC-MS/MS方法学体系，通过检测代谢反应体系的蛇葡萄素剩余浓度进行体外代谢反应条件的筛选和代谢规律的评价。结果 反应体系的孵育时间、肝微粒体浓度及蛇葡萄素浓度均对代谢产生影响，大鼠肝细胞色素P450亚酶CYP3A、CYP1A1/2和CYP2E1对蛇葡萄素代谢起主要作用。药用辅料对蛇葡萄素代谢的抑制作用呈剂量依赖性，其中聚氧乙烯氢化蓖麻油40、吐温80、聚维酮K30、羟丙基β环糊精、普朗尼克F68以混合竞争模式显著抑制蛇葡萄素的代谢。结论 这些药用辅料有望通过抑制代谢作用来提高蛇葡萄素的口服生物利用度。

Abstract:

OBJECTIVE To investigate the metabolic regularity of ampelopisn in rat liver microsomes and the effect of pharmaceutical excipients on its metabolism. METHODS The UPLC-MS/MS method was established to screen metabolic conditions in vitro and evaluate metabolic patterns by detecting the residual concentration of ampelopsin in the metabolic reaction system. RESULTS Ampelopisn metabolism was affected by incubation time, liver microsome concentration and initial ampelopisn concentration. Rat hepatocyte pigment P450 subenzyme CYP3A, CYP1A1/2 and CYP2E1 played a major role in serpentine metabolism. The inhibitory effect of pharmaceutical excipients on ampelopsin metabolism was dose-dependent manner. The metabolic kinetics studies revealed that Cremophor RH40, Tween 80, PVP K30, HPBCD and F68 exhibited significant inhibition metabolism in a mixed competition. CONCLUSION These pharmaceutical excipients are expected to improve the oral bioavailability of ampelopsin by inhibiting metabolism.