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学科主题物理化学
Glucuronidation of arbidol: identification of human UDP-glucuronosyltransferases and interaction potential
Fang ZZ(房中则); Yang L(杨凌); Ling Yang
会议名称9th International Meeting of the International-Society-for-the-Study-of-Xenobiotics
会议日期2010-9-4
2010-09-04
会议地点土耳其
页码62/2
部门归属十八室
主办者国际药物代谢学会
英文摘要Arbidol is an antiviral drug indicated for the prevention and treatment of all types of influenza infection and some other kinds of acute respiratory infections. It was marketed in Russia in 1993 and in China in 2006. Previous reports (Wang et al., 2008) have demonstrated that glucuronidation conjugation reaction was a major elimination pathway of arbidol. However, the UDP-glucuronosyltransferases (UGTs) involved in this process remains to be investigated. The present study aimed at identifying unambiguously the UGT isoforms involved in the production of arbidol O-glucuronide. Arbidol O-glucuronide was firstly isolated from a reaction mixture consisting of arbidol and human liver microsomes fortified with UDP-glucuronic acid (UDPGA) and elucidated by HPLC-MS/MS. The kinetic parameters were determined for pooled human liver microsomes (HLMs) and Vmax and Km values were calculated to be 2.03±0.05 nmol/min/mg protein and 8.0±0.7μM respectively. Assessment of a panel of recombinant UGT isoforms revealed the arbidol glucuronosyltransferase activity of UGT1A1, UGT1A3, UGT1A9. The results obtained from kinetic studies and chemical inhibition all demonstrated that UGT1A9 was a predominant UGT isoform involved in the glucuronidation of arbidol in HLM. Considering that UGT1A9 and UGT2B7 could metabolize many clinical drugs, inhibitory effects of arbidol on these two UGT isoforms were investigated. The results demonstrated that arbidol competitively inhibited UGT1A9 and UGT2B7. Ki values were calculated to be 3.5 μM (for UGT1A9) and 0.5 μM (for UGT2B7) when 4-MU was used as substrates. When propofol and 3’-azido-3’-deoxythymidine (AZT) were utilized as substrates for UGT1A9 and UGT2B7 respectively, Ki values were 29.7 μM (for UGT1A9) and 2.8 μM (UGT2B7). All these results were helpful for better understanding of arbidol’s pharmaceutical behaviour and its DDI potential.
语种中文
WOS记录号WOS:000281147700111
引用统计
文献类型会议论文
条目标识符http://cas-ir.dicp.ac.cn/handle/321008/114314
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
Fang ZZ,Yang L,Ling Yang. Glucuronidation of arbidol: identification of human UDP-glucuronosyltransferases and interaction potential[C],2010:62/2.
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