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学科主题: 物理化学
题名: Two Different Elimination Routes of Boc5 Mediated by Esterase and Albumin, Respectively, Play Varied Roles in Three Common Experimental Animals and Human
作者: Ge GB(葛广波) ;  Liang SC(梁思成) ;  Yang L(杨凌)
会议名称: 18th International Symposium on Microsomes and Drug Oxidations
会议日期: 2010-5-17
出版日期: 2010-05-17
会议地点: 中国
通讯作者: 杨凌
部门归属: 十八室
主办者: 国际异物质研究学会
摘要: As the first nonpeptidic agonist of glucagon-like peptide 1 receptor, Boc5 has been recognized as a potential candidate for treatment of diabetes, obesity and related metabolic problems [Chen D et al 2007; Su H et al 2008]. This study aimed to explore in vitro metabolic pathways of Boc5, as well as its plasma stability, in mouse, rat, minipig and human. The roles of three elimination pathways (esterase, CYP and UGT) in Boc5 metabolism were studied with liver microsomes obtained from mice (MLM), rats (RLM), minipigs (PLM) and humans (HLM). The plasma stability of Boc5 was also evaluated by using plasma from mice, rats, minipigs and humans. It was found that Boc5 can be metabolized to three hydrolyzed metabolites (M-1, M-2 and M-3) via an NADPH-independent pathway only in the presence of MLM, while it can be degraded to M-1 in plasma from human and three animals with different half lives (t1/2). Three metabolites (M-1, M-2, and M-3) were identified by liquid chromatography/mass spectrometry (LC/MS), based on their retention times and mass spectra compared with standards, and the consecutive loss of thiophene-2-carboxylic acid from the C-22 ester bond was revealed as the metabolic pathway of Boc5. The involved enzymes were determined by using a series of selective inhibitors and purified enzymes including human serum albumin and human butyrylcholinesterase, and the results revealed that two different enzymes participated in elimination of Boc5 in various species: a specific esterase in MLM was responsible for the hydrolysis of Boc5 in mice, while serum albumin-mediated hydrolysis plays an important role in human and rat. The hydrolytic rates of Boc5 in plasma from various plasma were also determined, the in vitro half-lives of Boc5 in plasma from human and rat are very similar (about 28 h), but Boc5 was more stable in porcine plasma with a very long t1/2 (> 83 h). The comparative studies on species differences in Boc5 hydrolysis also implied that rat might serve as an appropriate surrogate model for human, in toxicological, pharmacokinetic and pharmacodynamic related studies of this novel molecule.
语种: 中文
内容类型: 会议论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/114180
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,Yang L. Two Different Elimination Routes of Boc5 Mediated by Esterase and Albumin, Respectively, Play Varied Roles in Three Common Experimental Animals and Human[C]. 见:18th International Symposium on Microsomes and Drug Oxidations. 中国. 2010-5-17.
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