蓖麻油35和吐温80对瑞格列奈在2型糖尿病大鼠体内的药动学影响

Pharmacokinetics effects of tween 80 and cremophor EL 35 on Repaglinide in type 2 diabetes mellitus rats

目的探究药用辅料蓖麻油35与吐温80对瑞格列奈在2型糖尿病大鼠体内的药动学影响。方法腹腔注射40 mg·kg^(-1)链脲佐霉素构建2型糖尿病模型,在糖尿病大鼠组中分别单次或多次(连续14 d)静脉注射150 mg·kg^(-1)生理盐水、150 mg·kg^(-1)吐温80、43 mg·kg^(-1)蓖麻油35,而后给予4 mg·kg^(-1)瑞格列奈,检测特定时间点的血药浓度,并收集大鼠肝脏组织及血清,用于相关酶和转运体mRNA表达的分析、肝病理组织及肝生化检查。结果与对照组比较,单剂量给药条件下,辅料组的血药浓度和药动学参数无显著性差异;多剂量给药条件下,辅料组瑞格列奈在糖尿病大鼠体内的AUC显著上调。mRNA考察结果显示:在多剂量给药条件下,大鼠体内瑞格列奈的代谢相关酶CYP2C6、CYP2C22、CYP3A2均有显著下降。结论单剂量给予蓖麻油35和吐温80,瑞格列奈在大鼠体内的药动学过程无明显改变;在多剂量给药时,瑞格列奈在大鼠体内的药动学过程显著变化,除CYP3A1外,瑞格列奈的相关代谢酶均为显著抑制。

OBJECTIVE To investigate the potential pharmacokinetics effects of tween 80(T-80)and cremophor EL 35(EL-35)on Repaglinide(RGN)in type 2 diabetes mellitus(T2 DM)rats through intravenous administration.METHODS T2 DM rats model was induced by intraperitoneal injection of streptozotocin(40 mg·kg^(-1)).Then the T2 DM rats were intravenously administrated normal saline(150 mg·kg^(-1)),T-80(150 mg·kg^(-1)),EL-35(43 mg·kg^(-1))respectively,for single time and consecutive 14 days.After orally administrated RGN(4 mg·kg^(-1)),the blood sample was collected at predetermined time points,and the liver tissue and serum were collected for mRNA expression analysis and liver function detection after the pharmacokinetics assay.RESULTS There were no significant differences in pharmacokinetic parameters between excipient treated group and control group with single-dose administration.While in multiple-dose administration,the AUC of RGN in M-DMT and M-DME groups were both higher than M-DMC group.The mRNA expression results shown that,CYP2 C6,CYP2 C22 and CYP3 A2 in excipients treated group were significantly lower than M-DMC group.CONCLUSION The pharmacokinetic process of RGN in T2 DM rats is not significantly changed with single-dose treatment of T-80 and EL-35.However,the pharmacokinetic processes of RGN are changed in multiple-dose treatment,and some enzymes related to RGN metabolism were significantly inhibited.