Title:Metabolic Characteristics of SM-1, a Novel PAC-1 Derivative, in Human Liver Microsomes
Volume: 18
Issue: 2
Author(s): Ya Gong, Peiqi Wang, Jianming Li, Jingbin Huang*Jinsong Ding*
Affiliation:
- Department of Pharmacy, The Second Affiliated Hospital of Army Medical University, Chongqing, 400037, China
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, 410083, China
Keywords:
Human liver microsomes, SM-1, metabolism pathway, metabolic enzymes, chemical inhibition, PAC-1.
Abstract:
Background and Objectives: SM-1 is a new synthetic small molecular compound with
anti-tumor 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: 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.
Results: 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.
Conclusion: Through the identification of the biotransformation pathways and enzyme kinetics of
SM-1, the metabolic enzymes for SM-1 in HLMs are characterized.
