GPR119激动剂MBX-2982的小鼠药效学及大鼠体内药动学研究  

Pharmacology and Pharmacokinetics Studies of MBX-2982,A Novel GPR119 Agonists

作　　者：罗轶凡[1,2] 任利翔[3] 张英俊[3] 郑晓曦[3] 姜明燕[1,2] 

机构地区：[1]中国医科大学附属第一医院药学部,沈阳110001 [2]中国医科大学药学院,沈阳110001 [3]沈阳中海生物技术开发有限公司,沈阳110016

出　　处：《中国药学杂志》2015年第1期29-33,共5页Chinese Pharmaceutical Journal

摘　　要：目的研究GPR119激动剂MBX-2982对小鼠糖耐量的影响以及对KK-Ay小鼠各项指标的影响,评价其降糖效果,并进一步评价其在大鼠体内的吸收情况。方法以KM小鼠评价MBX-2982单次给药后对其糖耐量的影响;以KK-Ay小鼠体重、空腹血糖、糖耐量、甘油三酯、血清胰岛素为评价指标考察其药效情况;以大鼠进行不同剂量下的药动学实验,考察灌胃给予MBX-2982混悬液和溶液的吸收情况。结果正常小鼠糖耐量实验中,灌胃给予3、10、30 mg·kg-1的MBX-2982后均可降低各时间点的血糖值。MBX-2982以10、30 mg·kg-1剂量连续给药4周后,能显著降低KK-Ay小鼠的空腹血糖、降低血清甘油三酯、增加血清胰岛素水平,30 mg·kg-1剂量还能显著降低糖耐量实验中血糖曲线下面积。大鼠0.4%羧甲基纤维素混悬液4mg·kg-1灌胃给药后的绝对生物利用度约为35.2%,而二甲基亚砜-蓖麻油-生理盐水=1∶1∶8溶液4 mg·kg-1灌胃给药后的绝对生物利用度为98.2%。结论动物实验结果显示,MBX-2982作为GPR119激动剂有很好的降糖效果,其全溶溶液的口服生物利用度远高于混悬液,接近于100%。OBJECTIVE To observe the glucose tolerance and evaluate the hypoglycemic effect of MBX-2982 respectively in the normal mice and in the KK-AYmice. And further pharmacokineties investigation was experimented in rats. METHODS The influence of glucose tolerance was evaluated in KM mice which underwent a single dose of MBX-2982. Body weight, fasting blood glucose, glucose tolerance, triglyceride, serum insulin were all tested in order to evaluate the hypoglycemic effect on KK-AYmice. The pharmacokinetics of MBX-2982 suspension and solution were investigated in rats to calculate the oral bioavailability. RESULTS The blood glucose of each test point were all reduced after MBX-2982 （ 3,10, 30 mg kg -1 ） were administered orally to KM mice. After MBX-2982 （10, 30 mg kg-1） treatment to KK-Ay mice for 4 weeks, the fasting blood glucose and triglyceride were significantly reduced and the serum insulin was remarkably increased. Meanwhile the area under glucose curve was significant reduced of 30 mg kg-1. After oral administration of MBX-2982 （4 mg kg- 1 ） in rats, the oral bioavailability of suspension （0.4% CMC） and solution （ DMSO-Cremo- por EL-NS = 1 ： 1 ： 8 ） were 35.2% and 98. 2% receptively. CONCLUSION Animal experiment results show that the MBX-2982 as a GPR119 agonists had a good hypoglycemic effect. The absolute bioavailability of the solution is closed to 100%, which is higher than that of suspension.

关 键 词：MBX-2982 GPR119激动剂 KK-AY小鼠 空腹血糖 糖耐量 甘油三酯 血清胰岛素 生物利用度 

分 类 号：R965[医药卫生—药理学]