达塞布韦对扑热息痛葡萄糖醛酸化的抑制作用  

Inhibition of paracetamol glucuronidation by dasabuvir

作　　者：李兰丽 姜丽丽[1] 夏杨柳[1] 刘勇[1] LI Lanli;JIANG Lili;XIA Yangliu;LIU Yong(School of Life and Pharmaceutical Sciences,Dalian University of Technology,Panjin 124221,China)

机构地区：[1]大连理工大学生命科学与药学学院,辽宁盘锦124221

出　　处：《中国医科大学学报》2020年第10期887-892,共6页Journal of China Medical University

基　　金：国家重点研发计划(2017YFC1702006)。

摘　　要：目的探讨达塞布韦对扑热息痛(APAP)的葡萄糖醛酸化反应的抑制作用,定量预测2种药物同时服用时发生药物相互作用的危险性。方法利用人肝微粒体(HLMs)及重组人源尿苷二磷酸-葡萄糖醛酸转移酶1A9(UGT1A9),通过高效液相色谱法体外酶抑制动力学研究达塞布韦对APAP的葡萄糖醛酸化反应的作用。结果达塞布韦对APAP的葡萄糖醛酸化反应具有较强的非竞争性抑制作用。在HLMs中,其IC50和Ki值分别为(3.94±1.29)和(5.50±0.46)μmol/L。在重组人源UGT1A9中,达塞布韦对UGT1A9的IC50和Ki值分别为(5.24±1.26)和(4.92±0.46)μmol/L。利用体外实验数据及药物相互作用预测模型,预测当达塞布韦以250 mg、2次/d或更高剂量与APAP同时服用时,将导致APAP的曲线下面积至少增加27%。结论达塞布韦对APAP的葡萄糖醛酸化反应具有抑制作用,2种药物联合使用可能增加药物不良反应发生率。Objective To investigate the effects of dasabuvir on paracetamol glucuronidation and to quantitatively estimate the potential risk of drug-drug interactions due to UDP-glucuronosyltransferases(UGTs)inhibition.Methods The inhibition kinetics of dasabuvir were determined in human liver microsomes(HLMs)and recombinant human UGT1A9.The drug metabolites were detected using high performance liquid chromatography.Results Dasabuvir exhibited potent non-competitive inhibition against paracetamol glucuronidation.The IC50 and Ki values for dasabuvir in HLMs were 3.94±1.29μmol/L and 5.50±0.46μmol/L,respectively.The IC50 and Ki values in recombinant human UGT1A9 were 5.24±1.26μmol/L and 4.92±0.46μmol/L,respectively.The data obtained from in vitro experiments in conjunction with drug interaction prediction models showed that co-administration of dasabuvir(250 mg twice daily or higher)with paracetamol resulted in at least a 27%increase in the area under curve of paracetamol.Conclusion Dasabuvir has an inhibitory effect on glucuronidation of paracetamol.Co-administration of dasabuvir with paracetamol may lead to higher frequency of adverse drug reactions.

关 键 词：尿苷二磷酸葡萄糖醛酸转移酶 扑热息痛 达塞布韦 药物相互作用 

分 类 号：R969.2[医药卫生—药理学]