比阿培南在人肝微粒体、人肾S9和体外人血浆中的稳定性及其代谢产物鉴定  

Metabolic stability of biapenem in human liver microsomes, human kidney S9 fractions and human blank plasma and analysis of its metabolites

作　　者：李文艳[1] 刘艳辉[1] 董婧[1] LI Wen-yan;LIU Yan-hui;DONG Jing(Department of Pharmacy,Shanghai Pudong New Area Gongli Hospital,Shanghai 200135,China)

机构地区：[1]上海市浦东新区公利医院药剂科,上海200135

出　　处：《中国医院药学杂志》2021年第8期807-811,共5页Chinese Journal of Hospital Pharmacy

基　　金：国家自然科学基金(编号:81803632);上海市浦东新区卫生计划生育委员会临床药学重点学科建设项目(编号:PWZxK2017-13);上海市浦东新区公利医院拔尖人才培养计划(编号:GLRb2020-01)。

摘　　要：目的:考察比阿培南在人肝微粒体、人肾S9和体外人空白血浆中的代谢稳定性,并推测代谢产物的结构及可能的代谢途径。方法:采用高效液相色谱-串联质谱联用仪(HPLC-MS/MS)检测比阿培南分别与人肝微粒体、人肾S9和人空白血浆孵育后孵育液中剩余的比阿培南含量,比较代谢稳定性。此外,利用快速液相色谱-离子阱-飞行时间质谱联用仪(UFLC/MS-IT-TOF)分析比阿培南与人肝微粒体和人肾S9孵育后的提取离子流图,比较差异峰并通过质谱图推测代谢产物和代谢途径。结果:比阿培南与人肝微粒体、人肾S9和人空白血浆孵育120 min后的剩余百分比分别为(89.2±2.66)%、(52.0±7.6)%和(96.3±5.4)%,计算得到其在人肝微粒体和人肾S9中代谢的体外消除半衰期(t_(1/2))分别为1 046.2和120.9 min,在人肝微粒体中固有清除率(C_(Lint, h))和人肾S9中固有清除率(CLint, R)分别为0.57和2.05 mL·min^(-1)·kg^(-1),肝清除率(C_(Lh))和肾代谢清除率(CL_(R))分别为0.53和1.72 mL·min^(-1)·kg^(-1)。此外,比阿培南在人肝微粒体和人肾S9孵育体系中都只鉴定出1个体外代谢产物,推测比阿培南的主要代谢途径为β-内酰胺环水解。结论:比阿培南主要在人肾S9中代谢,少量在人肝微粒体中代谢,产生的代谢物为β-内酰胺环水解产物。OBJECTIVE To explore the metabolic stability of biapenem in human liver microsomes, human kidney S9 fractions and human blank plasma to analyze the possible metabolic pathways and its metabolites in vitro.METHODS HPLC-MS/MS was employed for detecting the residual biapenem content in the incubation solution after incubating with human liver microsomes, human kidney S9 fractions and human blank plasma.Furthermore, extracted ion flow chromatogram of biapenem in incubation solution of human liver microsomes and human kidney S9 fractions was determined by UPLC/MS-IT-TOF for predicting the possible metabolic pathways and metabolites. RESULTS The residual percentage of biapenem in incubation solution was(89.2±2.66)%,(52.0±7.6)% and(96.3±5.4)% respectively after 120 min incubating with human liver microsomes, human kidney S9 fractions and human blank plasma.The estimated elimination half-life of biapenem(t_(1/2))in human liver microsomes and human kidney S9 fractions were 1046.2 and 120.9 min respectively.The intrinsic clearance rates(C_(Lint, h))of biapenem in human liver microsomes and human kidney S9 fractions(CLint, R)were 0.57 and 2.05 mL·min^(-1)·kg^(-1).Liver clearance(C_(Lh))and renal metabolic clearance(CL_(R))of biapenem in human liver microsomes and human kidney S9 fractions were 0.53 and 1.72 ml·min^(-1)·kg^(-1).Only one metabolite(M1)of biapenem was detected in both human liver microsomes and human kidney S9 fractions incubation systems.It is speculated that the major metabolic pathway of biapenem was the hydrolysis of β-lactam ring.CONCLUSION Biapenem is metabolized predominantly in human kidney S9 fractions and partially in human liver microsomes.And the metabolite is the hydrolysate of β-lactam ring.

关 键 词：比阿培南 人肝微粒体 人肾S9 人空白血浆 代谢稳定性 代谢产物鉴定 

分 类 号：R966[医药卫生—药理学]