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Aim To investigate the effect of SM-1 on seven main cytochrome P450(CYP450)in human liver microsomes.Methods Substrate or SM-1 was incubated with human liver microsomes for 30 min in vitro,and divided into control group and experimental group.The effects of SM-1 on the main phase I metabolic enzymes in human liver microsomes was detected by HPLC.Phenacetin,bupropion,paclitaxel,tolbutamide,omeprazole,dextromethorphan,testosterone were investigated as probe drugs.Results Inhibition rate of SM-1 on the classical substrate of human liver microsomal CYP was 0.05％,3.37％,0.08％,2.07％,4.20％,-0.15％and 10.84％,respectively.Conclusions SM-1 may have inhibitory effect on CYP3A4.Attention should be paid to the interaction of clinical drug induced by CYP enzyme inhibition.
RESUMO
Objective To investigate the antitumor activity of the procaspase-3 activator SM-1 in BGC-823 cells in vivo and in vitro and the mechanisms.Methods The inhibitory effects of SM-1 on proliferation of BGC-823 cells were evaluated using MTT method, the cell apoptosis rate was detected by flow cytometry, and the expression of caspase-3 protein and procaspase-3 mRNA was detected by Western blotting and RT-PCR, respectively.SM-1 Antitumor activity was evaluated using the xenograft of BGC-823 cells in nude mice.Results SM-1 effectively inhibited the proliferation in vitro and in-duced apoptosis of BGC-823 cells in a dose-dependent manner.After treatment with SM-1 for 48 h, the protein expression levels of caspase-3 and mRNA expression levels of procaspase-3 were increased.SM-1 significantly inhibited growth of BGC-823 xenograft tumor at the 300 mg/kg dose and the inhibition rate was 56.3%(P<0.05).Conclusion SM-1 can significantly inhibit the tumor growth of BGC-823 cells in vivo and in vitro.The mechanism is possibly related to the activation of procaspase-3 and induced apoptosis of tumor cells.
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Aim To study absorption characteristics of SM-1 , a novel anti-tumor agent , to provide a research basis for the druggability evaluation of SM-1 and formu-lation design. Methods Caco-2 cell monolayer model and in situ single-pass intestinal perfusion rat model were used to study the absorption characteristics of SM-1 , and the absorption of SM-1 in vivo was evaluated through absolute bioavailability study in rats. Results The results of cell monolayer model showed that cu-mulative absorption and efflux of SM-1 increased line-arly with concentration ( 10 ~40 mg · L-1 ) . There were no significant differences in Papp with different concentrations ( P>0. 05 ) . SM-1 was absorbed mainly through passive diffusion. The intestinal perfusion re-sults showed that Ka and Pef of SM-1 had no significant differences ( P > 0. 05 ) , when the concentrations ranged from 25 to 100 mg · L-1 . SM-1 entered the systemic circulation mainly via on passive diffusion, indicating it is a compound with high permeability. The absorption of SM-1 in duodenum was superior to other intestinal segments ( P 0. 05 ) . The absolute bioavailability of SM-1 in rats was 29. 3%. Conclusion The membrane perme-ability of SM-1 is high and it can be absorbed by intes-tine well. The absorption mechanism of SM-1 is pas-sive diffusion, and it possibly escapes from the efflux transporter protein. The absolute bioavailability of SM-1 in rats is low.