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学科主题物理化学
In Vitro Metabolic Study of Boc5 in human tissues and Animal Liver Microsomes
Ge GB(葛广波); Liang SC(梁思成); Liu Y(刘勇); Yang L(杨凌); Ling Yang
会议名称3rd Asian Pacific Regional Meeting of the International-Society-for-the-Study-of-Xenobiotics
会议日期2009-5-10
2009-05-10
会议地点泰国
页码102/2
部门归属十八室
主办者International-Society-for-the-Study-of-Xenobiotics
英文摘要As the first nonpeptidic agonist of glucagon-like peptide 1 receptor, Boc5 can invoke sustained glycemic control and weight loss in diabetic C57BL/6J mice, and has become a promising hit compound for antidiabetic drug. Boc5 displays good efficiency via i.v. administration but loss efficiency via oral administration, thus its ADME properties should be studied. In the present study, the in vitro investigation on metabolic stability of Boc5 was first reported. Both phase I and phase II metabolic studies were carried out by using a series of tissues and microsomes from human and three experimental animals including pig, rat and C57BL/6J mice. Significant species difference in metabolism of Boc5 was presented, Boc5 can not be metabolized by human plasma, liver and intestine microsome, as well as rat and pig liver microsomes. In contrast, Boc5 can be rapid metabolized by C57BL/6J mice liver microsome (~50% conversion at 1 h), and three metabolites (M-1, M-2, and M-3) were detected by using liquid chromatography/mass spectrometry (LC/MS). M-1 was confirmed as 2-thenoic acid, and M-3 and M-2 were assigned as two metabolites after hydrolysis of one and two thenoic acids from Boc5, respectively, based on the retention times and mass spectra by comparison with standards. These results revealed that the hydrolysis of thiophene carboxylic ester bond was the major metabolic pathway of Boc5, indicating esterases invlolved in this biotransformation. Further studies have shown that carboxylesterase in C57BL/6J mice liver display the key role in rapid hydrolysis of Boc5 by using a range of inhibitors. All of these results were very useful to develop the next generation nonpeptidic agonists and to choose suitable experimental animal for whole tests.
语种中文
WOS记录号WOS:000269483300212
引用统计
文献类型会议论文
条目标识符http://cas-ir.dicp.ac.cn/handle/321008/113590
专题中国科学院大连化学物理研究所
通讯作者Ling Yang
推荐引用方式
GB/T 7714
Ge GB,Liang SC,Liu Y,et al. In Vitro Metabolic Study of Boc5 in human tissues and Animal Liver Microsomes[C],2009:102/2.
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