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Current Pharmaceutical Analysis


ISSN (Print): 1573-4129
ISSN (Online): 1875-676X

Research Article

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

Author(s): Ya Gong, Peiqi Wang, Jianming Li, Jingbin Huang* and Jinsong Ding*

Volume 18, Issue 2, 2022

Published on: 02 March, 2021

Page: [182 - 192] Pages: 11

DOI: 10.2174/1573412917666210302145158


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.

Keywords: Human liver microsomes, SM-1, metabolism pathway, metabolic enzymes, chemical inhibition, PAC-1.

Graphical Abstract
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