荭草苷对UGT1A1代谢伊立替康的抑制作用  

Inhibitory effect of orientin on Irinotecan metabolism mediated by UDP-glucuronosyltransferase 1A1

作　　者：李铭 孙华 沈雯 李巍 LI Ming;SUN Hua;SHEN Wen;LI Wei(Translational Medicine Research Institute,Yangzhou University Medical Academy,Jiangsu Province,Yangzhou225009,China)

机构地区：[1]扬州大学医学院转化医学研究院,江苏扬州225009

出　　处：《中国当代医药》2024年第22期4-7,22,共5页China Modern Medicine

基　　金：国家自然科学基金面上项目(82274006);扬州大学大学生科创基金项目(XCX20230818)。

摘　　要：目的探究荭草苷对野生型尿苷二磷酸葡萄糖醛酸转移酶1A1(UGT1A1)及其常见突变体UGT1A1*6酶活性的影响,定量预测含有荭草苷的中草药与伊立替康同时服用时发生草药-药物相互作用的风险。方法建立体外孵育体系,将系列浓度的荭草苷与SN-38共同孵育,用超高效液相色谱-串联质谱法(UPLC-MS/MS)测定SN-38代谢产物SN-38葡萄糖醛酸酯(SN-38G)的生成速率,考察荭草苷对SN-38葡萄糖醛酸化的影响。结果荭草苷对UGT1A1*1和UGT1A1*6的半抑制浓度(IC50)分别为19.04、34.35μmol/L,计算得到的Ki值分别为9.32、19.63μmol/L。利用体外-体内外推法(IVIVE)定量预测表明口服含有荭草苷的中草药与伊立替康联合使用时,会导致SN-38的血浆浓度-时间曲线下面积(AUC)至少增加87%。结论荭草苷有可能抑制UGT1A1的活性而引发伊立替康的不良反应,为合理使用含荭草苷的中草药与伊立替康提供了理论指导。Objective To explore the effects of orientin on the enzyme activity of wild type UDP-glucuronosyltransfer-ase1A1(UGT1A1)and its common mutant UGT1A1*6,and to predict the risk of herb-drug interaction between orientin and Irinotecan.Methods In vitro incubation system was established,polygonin was incubated with SN-38,the production rate of SN-38 glucuronide(SN-38G)was determined by ultra-performance liquid chromatography tandem mass spectrometry(UPLC-MS/MS),and the effect of polygonin on the glucoaldehyde acidification of SN-38 was investigated.Results The half-maximal inhibitory concentration(IC50)of orientin was 19.04μmol/L for UGT1A1*1 and 34.35μmol/L for UGT1A1*6,and the calculated Ki values were 9.32 and 19.63μmol/L,respectively.Quantitative predictions using in vitro-in vivo extrapolation(IVIVE)showed that oral polygonin-containing herbal medicine combined with Irinotecan resulted in an increase of at least 87%in the plasma concentration-time area under curve(AUC)of SN-38.Conclusion Orientin may inhibit the activity of UGT1A1 and lead to the adverse reaction of Irinotecan,which provides a theoretical guide for rational use of Chinese herbal medicine containing orientin and Irinotecan.

关 键 词：荭草苷 尿苷二磷酸葡萄糖醛酸转移酶1A1 伊立替康 草药-药物相互作用 

分 类 号：R286[医药卫生—中药学] R969.1[医药卫生—中医学]