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K_i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K_i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。

达塞布韦对扑热息痛葡萄糖醛酸化的抑制作用

李兰丽, 姜丽丽, 夏杨柳, 刘勇

大连理工大学生命科学与药学学院, 辽宁 盘锦 124221

收稿日期:2019-08-23出版日期:2020-10-30发布日期:2020-10-13
通讯作者:刘勇E-mail:yliu@dlut.edu.cn
作者简介:李兰丽(1989-),女,硕士研究生.
基金资助:国家重点研发计划（2017YFC1702006）


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
Abstract: 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 K_i values for dasabuvir in HLMs were 3.94±1.29 μmol/L and 5.50±0.46 μmol/L,respectively. The IC₅₀ and K_i values in recombinant human UGT1A9 were 5.24±1.26 μmol/L and 4.92±0.46 μmol/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.
Key words: UDP-glucuronosyltransferases, paracetamol, dasabuvir, drug-drug interactions
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