Stability Study of Novel Hypoglycemic Compound LSM- 13 in Rat Liver Microsomes and Its Metabolites Analysis / 中国药房

ABSTRACT

OBJECTIVE：To i nvestigate the metabolism stabilities of novel hypoglycemic compound LSM- 13 in rat liver microsomes，and to analyze the possible metabolites. METHODS ：LSM-13 was dissolved in rat liver microsome incubation system initiated by reduced nicotinamide adenine dinucleotide phosphate ，and was incubated in water at 37 ℃. The reaction was terminated with acetonitrile at 0，5，10，15，30，45 and 60 min，respectively. Using indomethacin as internal standard ，the concentration of LSM-13 in incubation system was determined by HPLC. The residual percentage and enzyme kinetic parameters of LSM- 13 were calculated at different incubation time points with the concentration of LSM- 13 incubated for 0 min as reference. UPLC-Q-TOF/MS was used to analyze and speculate the metabolites of LSM- 13 in rat liver microsomes. RESULTS ：After 60 min incubation ，the remaining percentage of LSM- 13 was（56.07±0.95）％，the half-life was 42.78 min，and the intrinsic clearance was 0.032 4 mL/（min·mg）. Compared with total ion flow diagram of rat liver microsome blank samples ，three chromatographic peaks were added in the samples incubated for 60 min；the corresponding molecular ion peaks were m/z 505.133 8，417.102 4，293.111 7 [M+H]+；the possible metabolites may be dehydrogenation ，O-debentylation and hydrolysis products of LSM- 13. CONCLUSIONS ： The compound LSM- 13 has moderate stability in rat liver microsomes ，and may undergo dehydrogenation ，O-debentylation and hydrolysis.