Ya Gong*, Peiqi Wang, Jianming Li and Jinsong Ding Pages 1 - 11 ( 11 )
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.
human liver microsomes, SM-1, metabolism pathway, metabolic enzymes, chemical inhibition
Department of Pharmacy, The Second Affiliated Hospital of Army Medical University, Chongqing 400037, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410083, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410083, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410083