基于procaspase-3激活的抗肿瘤活性分子SM-1吸收机制研究

Absorption mechanism of SM-1: a procaspase-3-activated anti-tumor agent

摘要：目的初步探讨新型抗肿瘤活性分子SM-1的吸收特征，为其成药性评价以及剂型设计提供研究基础。方法分别采用Caco-2细胞模型及大鼠在体肠灌流模型研究SM．1吸收特征，并通过大鼠体内药动学研究综合评价SM-1在体内的吸收程度。结果在10—40mg·L。时SM-1的吸收以被动扩散为主，其双向转运过程可能与浓度无关。在25—100mg·L。内，SM-1的K与Peff差异无显著性（P〉0．05），说明药物吸收无自身浓度抑制作用，SM-1的小肠吸收表现为被动扩散机制，属于高渗透性化合物。SM-1在十二指肠吸收优于其他肠段（P〈0．05），在空肠、回肠、结肠的吸收差异无显著性（P〉0．05）。初步药动学研究显示，SM-1在大鼠体内绝对生物利用度为29．3％。结论SM-1渗透性高，在肠道内吸收良好，且吸收机制主要以被动扩散为主，不受转运蛋白外排作用影响，大鼠体内绝对生物利用度较低。

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 Paop with different concentrations （ P 〉 0. 05 ）. SM-1 was absorbed mainly through passive diffusion. The intestinal perfusion re- sults showed that Ka and Poff of SM-1 had no significant differences （ P 〉 0.05 ）, when the concentrations ranged from 25 to 100 mg ~ L-~. SM-1 entered thesystemic 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 ） , there were no significant differences in the jejunum, ileum and colon （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.