细胞色素P4503A4酶介导的水飞蓟素对吉非替尼代谢的影响  

Effect of silybin on gefitinib metabolism mediated by cytochrome P4503A4 enzyme

作　　者：李珊 路明 柳熠鑫 任菲菲 李相晨 张志清[1] LI Shan;LU Ming;LIU Yi-xin;REN Fei-fei;LI Xiang-chen;ZHANG Zhi-qing(Department of Pharmacy,The Second Hospital of Hebei Medical University,Shijiazhuang 050000,Hebei Province,China)

机构地区：[1]河北医科大学第二医院药学部,河北石家庄050000

出　　处：《中国临床药理学杂志》2023年第11期1587-1591,共5页The Chinese Journal of Clinical Pharmacology

基　　金：河北省财政厅、河北省卫生计生委政府资助临床医学优秀人才培养和基础课题资助项目(冀财社[2017]46号)。

摘　　要：目的考察人混合肝微粒体中吉非替尼的酶促反应动力学,探究水飞蓟素对吉非替尼代谢的影响。方法建立吉非替尼人肝微粒体体外孵育体系,用LC-MS/MS法测定体系中吉非替尼的剩余浓度,计算酶促反应动力学参数,如米氏常数(K_(m))、最大反应速率(V_(max))以及固有清除率(C_(Lint))。将系列浓度的水飞蓟素与吉非替尼共同孵育,测定水飞蓟素对吉非替尼代谢的半数抑制浓度(IC_(50))。结果在体外人肝微粒体中,测得吉非替尼的K_(m)为57.12μmol·L^(-1),V_(max)为21.09 nmol·min^(-1)·mg protein-1,C_(Lint)为0.37 mL·min^(-1)·mg^(-1)。水飞蓟素在0.5~50.0μg·mL^(-1)内对吉非替尼的代谢具有剂量依赖性的抑制作用,其IC_(50)值为20.74μg·mL^(-1)。结论水飞蓟素可剂量依赖性地抑制吉非替尼在人肝微粒体中的代谢,两药合用应密切关注可能发生的药物相互作用。Objective To investigate the enzymatic reaction kinetics of gefitinib in mixed liver microsomes of human,and to explore the effect of silymarin on the metabolism of gefitinib.Methods The incubation system of human liver microsomes containing gefitinib was established,and the residual concentration of gefitinib in the system was determined by LC-MS/MS method.The kinetic parameters of enzymatic reaction such as michaelis constant(K_(m)),maximum reaction rate(V_(max))and intrinsic clearance(C_(Lint))were calculated.The median inhibitory concentration(IC_(50))of silymarin on gefitinib metabolism was determined.Results The K_(m),V_(max) and C_(Lint) of gefitinib incubated in human liver microsomes were 57.12μmol·L^(-1),21.09 nmol·min^(-1)·mg protein-1 and 0.37 mL·min^(-1)·mg^(-1),respectively.Silymarin inhibited the metabolism of gefitinib dose-dependently within 0.5-50.0μg·mL^(-1) and the IC_(50) value was 20.74μg·mL^(-1).Conclusion Silymarin can inhibit the metabolism of gefitinib in human liver microsomes in a dose-dependent manner,suggesting that close attention should be paid to the possible interaction between the two drugs in clinical application.

关 键 词：吉非替尼 水飞蓟素 人肝微粒体 细胞色素P4503A4 酶促反应动力学 

分 类 号：R28[医药卫生—中药学]