维罗非尼对UGT1A1介导的伊立替康代谢的抑制作用研究

目的:应用体外人肝微粒体及重组人源代谢酶孵育体系观察维罗非尼对尿苷二磷酸葡萄糖醛酸基转移酶1A1（UDP-glucuronosyltransferases,UGT1A1）介导的伊立替康代谢的抑制作用，通过体外-体内外推（in vitro-in vivo extrapolation,IV-IVE）预测体内药物-药物相互作用（drug-drug interaction,DDI）的发生风险。方法:以混合人肝微粒体 （human liver microsomes,HLMs）及重组表达的人UGT1A1 作为酶源，观察维罗非尼对UGT1A1介导的伊立替康活性代谢产物SN-38葡糖醛酸化反应的抑制作用，求得半数最大抑制浓度（half maximum inhibitory concentration,IC50）和抑制动力学常数Ki及抑制类型；并基于体外参数预测了体内维罗非尼与伊立替康联合应用引发的潜在DDI风险。结果:维罗非尼对UGT1A1具有较强的非竞争性抑制作用，IC50 为4.35 μmol/L，Ki为9.77 μmol/L。口服治疗剂量的维罗非尼 （960 mg，每日两次）可导致SN-38的药时曲线下面积（area under the curve,AUC）增加7%～149% 。结论:维罗非尼与伊立替康联合应用时，可通过强效抑制UGT1A1而影响伊立替康在体内的代谢清除，具有引发DDI的风险。

Inhibitory effect of vemurafenib on UGT1A1-mediated irinotecan metabolism

AIM: To study the inhibitory effect of vemurafenib on UDP-glucuronosyltransferases 1A1 (UGT1A1)-mediated irinotecan metabolism, and predict the risk of drug-drug interactions (DDI) by in vitro-in vivo extrapolation (IV-IVE). METHODS: A panel of human liver microsomes (HLMs) and recombinant human UGT1A1 were used to characterize the inhibitory effect of vemurafenib on human UGT1A1-mediated glucuronidation of SN-38, the active metabolite of irinotecan. The half maximum inhibitory concentration (IC50) and the constant of inhibition kinetics (Ki) were obtained, and the potential risk of DDI was predicted based on in vitro parameters. RESULTS:Vemurafenib had strong non-competitive inhibitory effect on UGT1A1, the IC50 value was 4.35 μmol/L, and the inhibition kinetic constant Ki value was 9.77 μmol/L. The area under the curve (AUC) ratio of SN-38 can be increased by 7% to 149% at the oral dose of 960 mg twice daily. CONCLUSION: The strong inhibition of vemurafenib on UGT1A1 leads to reduction of the UGT1A1-mediated irinotecan metabolism, and increases the risk of DDI.