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

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...

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

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(CL_int,h) of biapenem in human liver microsomes and human kidney S9 fractions(CL_int,R) were 0.57 and 2.05 mL·min^-1·kg^-1.Liver clearance(CL_h) 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.