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学科主题: 物理化学
题名: In Vitro Metabolic Study of Boc5 in human tissues and Animal Liver Microsomes
作者: Ge GB(葛广波) ;  Liang SC(梁思成) ;  Liu Y(刘勇) ;  Yang L(杨凌)
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
出版日期: 2009-05-10
会议地点: 泰国
通讯作者: Ling Yang
部门归属: 十八室
主办者: International-Society-for-the-Study-of-Xenobiotics
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
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内容类型: 会议论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/113590
Appears in Collections:中国科学院大连化学物理研究所_会议论文

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Recommended Citation:
Ge GB,Liang SC,Liu Y,et al. In Vitro Metabolic Study of Boc5 in human tissues and Animal Liver Microsomes[C]. 见:3rd Asian Pacific Regional Meeting of the International-Society-for-the-Study-of-Xenobiotics. 泰国. 2009-5-10.
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