In vitro metabolism of BYZX in human liver microsomes and the structural elucidation of metabolite by liquid chromatography–mass spectrometry method

2007 ◽  
Vol 857 (2) ◽  
pp. 266-274 ◽  
Author(s):  
Zong-ling Xia ◽  
Jing-yan Ying ◽  
Rong Sheng ◽  
Su Zeng ◽  
Yong-zhou Hu ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Liquid Chromatography ◽  
Human Liver ◽  
Liver Microsomes ◽  
Human Liver Microsomes ◽  
In Vitro Metabolism ◽  
Liquid Chromatography Mass Spectrometry ◽  
Spectrometry Method ◽  
Mass Spectrometry Method

Metabolic Characteristics of SM-1, a Novel PAC-1 Derivative, in Human Liver Microsomes

2021 ◽  
Vol 17 ◽  
Author(s):  
Ya Gong ◽  
Peiqi Wang ◽  
Jianming Li ◽  
Jinsong Ding
Keyword(s):  
Mass Spectrometry ◽  
Liquid Chromatography ◽  
Enzyme Kinetics ◽  
Human Liver ◽  
Liver Microsomes ◽  
Human Liver Microsomes ◽  
Spectrometry Method ◽  
Mass Spectrometry Method ◽  
Metabolic Characteristics ◽  
Kinetics Of

Background and Objectives: SM-1 is a new synthetic small molecule compound with antitumor activity. The metabolism of SM-1 is a key parameter that needs to be evaluated to provide further insight into drug safety and efficacy in the early phases of drug development. Methods and Results: In this study, the biotransformation process of SM-1 including the metabolic pathways and major metabolites was investigated based on a liquid chromatography-mass spectrometry method. Upon incubation of SM-1 with human liver microsomes, five metabolites were identified, namely dihydrodiol formation (R1), hydroxylation (R2, R3 and R5), and debenzylation (R4) of SM-1, with R1 and R4 being the major metabolites. The enzyme kinetic parameters of SM-1 were determined by a liquid chromatography tandem mass spectrometry method. The enzyme kinetics of SM-1 obeyed the Michaelis-Menten equation. The Vmax, Km, and CLint of SM-1 in HLMs were 14.5 nmol/mg protein/h, 6.32 μM, and 2.29 mL/mg protein/h, respectively. The chemical inhibition studies showed that CYP450 isoenzymes were responsible for SM-1 metabolism in HLMs and CYP3A4 was the major CYP450 isoenzyme involved in the metabolism of SM-1; these findings were confirmed by using the human recombinant CYP3A4. Conclusions : Through identification of the biotransformation pathways and enzyme kinetics of SM-1, the metabolic enzymes for SM-1 in HLMs are characterized.

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