中文摘要：

目的考察包含表面活性剂Cremophor RH40的自微乳化给药系统（SMEDDS）对大鼠体内细胞色素P450（CYP3A）活性的影响。方法以咪达唑仑（MDZ）为模型药物,采用高效液相色谱（HPLC）法测定MDZ及其活性代谢物1＇-羟基咪达唑仑在大鼠体内的血药浓度,并计算其药动学参数,考察MDZ自乳化微乳对大鼠体内CYP3A活性的影响,同时采用蛋白免疫印迹法检测上述制剂对大鼠肠黏膜上CYP3A蛋白表达的影响。结果 MDZ微乳的口服生物利用度为MDZ片的3.14倍,且显著降低1′-羟基咪达唑仑与咪达唑仑血浆浓度-时间曲线下面积（AUC）0-∞的比值（由0.25减少到0.11,P〈0.05）;MDZ自微乳化制剂还可显著延长MDZ在体内的平均滞留时间（MRT）及半衰期（t1/2）[MRT由（0.63±0.13）h延长至（1.23±0.38）h;t1/2由（0.33±0.11）h延长至（0.65±0.25）h,P〈0.05];相对于MDZ片,SMEDDS口服给药后,肠道CYP3A的蛋白表达水平显著降低。结论含有Cremophor RH40的SMEDDS能抑制大鼠体内CYP3A的代谢,从而提高CYP3A底物药物的口服生物利用度。

英文摘要：

Objective To evaluate the effect of Cremophor RH40-based self-microemulsiflying drug delivery system（SMEDDS）on the activity of CYP3A in rats.Methods The pharmacokinetics parameters for midazolam（MDZ）,as a probe,and its metabolite 1＇-hydroxymidazolam were estimated from the plasma concentrations determined by HPLC.Effects of the SMEDDS on the intestinal CYP3A enzymes activity was detected by western blot analysis.Results The pharmacokinetics parameters showed that oral bioavailability of MDZ in microemulsion was 3.14-fold higher than that of Dormicum,and which inhibited the activity of CYP 3A by decreasing the ratio of AUC0-∞（1＇-OH-MDZ）/AUC0-∞（MDZ）in comparison to Dormicum（0.11 vs.0.25,P0.05）.MRT and t1/2 of MDZ were obviously prolonged in MDZ microemulsion-treated group compared with Dormicum group [MRT：（1.23±0.38）vs.（0.63±0.13）h;t1/2：（0.65±0.25）vs.（0.33±0.11）h,P0.05].A significant decrease in CYP3A protein expression was observed in rat intestine mucosa treated with microemulsion.Conclusion It was found that the Cremophor RH40-based SMEDDS inhibited the activity of CYP3A and significantly improved the oral bioavailability of MDZ in rats.