斑蝥酸钠维生素B_6和复方苦参注射液对人肝微粒体细胞色素P450酶活性的抑制作用  

Inhibitory effects of compound sophora and disodium cantharidinate and vitamin B_6 injections on the activity of cytochrome P450 enzymes in human liver microsomes

作　　者：蔡小军[1] 黄凯[1] 宋惠珠[1] 温浩[1] 洪远[1] 

机构地区：[1]南京医科大学附属无锡市人民医院药学部,江苏无锡214023

出　　处：《中国临床药理学杂志》2017年第21期2150-2153,共4页The Chinese Journal of Clinical Pharmacology

基　　金：江苏省药学会医院药学基金资助项目(201409)

摘　　要：目的考察斑蝥酸钠维生素B_6和复方苦参注射液对人肝微粒体细胞色素P450酶(CYP450)7种同工酶活性的体外抑制作用。方法将66.70%,33.40%,16.70%,6.67%,2.22%,7.41‰,2.47‰浓度的斑蝥酸钠维生素B_6和100.00%,50.00%,25.00%,10.00%,3.33%,1.11%,3.70‰复方苦参注射液分别与人肝微粒体进行孵育,以非那西丁、双氯芬酸、(S)-美芬妥英、右美沙芬、咪达唑仑、安非他酮、阿莫地喹分别作为CYP1A2、CYP2C9、CYP2C19、CYP2D6、CYP3A4、CYP2B_6、CYP2C8的探针底物,用LC-MS/MS检测探针底物代谢物的生成量,计算半数抑制浓度(IC_(50))。结果斑蝥酸钠维生素B_6注射液对CYP450亚型活性的IC_(50)>10 mg,远高于其日用药量(0.1~0.5 mg)。复方苦参注射液对CYP1A2和CYP2D6的IC_(50)值分别是15.2,10.3 mL,均小于其日用药量(20mL);对CYP2C8和2C19的IC_(50)值均为21.1 mL,均接近其日用药量;对CYP2B_6、2C9、3A4-M和3A4-T的IC_(50)值分别为63.5,72.0,95.5,92.5 mL,均远高于其日用药量(20 mL)。结论临床剂量下,斑蝥酸钠维生素B_6注射液在体外对CYP450亚型活性无影响;复方苦参注射液在体外对CYP1A2和CYP2D6均有明显的抑制作用,对2C8和2C19均有一定程度的抑制作用,对CYP2B_6、2C9、3A4-M和3A4-T均无明显的抑制作用。临床静脉用复方苦参注射液时,应注意可能因CYP450酶抑制引起的药物相互作用。Objective To evaluate the inhibitive effects of disodium cantharidinate and vitamin B6 and compound sophora injections on 7 main cytochrome P450（ CYP450） isoforms in human microsomes in vitro for predicting the drug-drug interactions in clinical application. Methods Different concentrations of test disodium cantharidinate and vitamin B6 and compound sophora injections were incubated with human microsomes. phenacetin,bupropion,amodiaquine,（ S）-mephenytoin,dextromethorphan,midazolam,testosterone were used as the substrates of CYP1 A2,CYP2 C9,CYP2 C19,CYP2 D6,CYP3 A4-M,2 B6,2 C8 and CYP3 A4-T,respectively. After the co-incubation,the metabolite of each substrate was analyzed by LC-MS/MS assay and then hemi-inhibitory concentration（ IC50） was calculated. Results IC50 values（〉10 mg） of disodium cantharidinate and vitamin B6 were totally exceed itsdaily-dose（ 0. 1-0. 5 mg）. IC50 values of compound sophora injection on CYP1 A2,2 D6,2 C8,2 C19 were 15. 2,10. 3,21. 1 and 21. 1 mL,respectively,which were less than or near to its daily-dosage. However,compound sophora injection＇s IC50 values on CYP2 B6,2 C9,3 A4-M and 3 A4-T were 63. 5,72. 0,95. 5,92. 5 mL,which were much higher than its daily-dosage（ 20 mL）. Conclusion Disodium Cantharidinate and vitamin B6 showed no inhibition on7 main CYP450 isoforms in vitro at clinical normal dosage,while the inhibitory effects of compound sophora injection on the activities of CYP1 A2,2 D6,2 C8,2 C19 were strong and medium,respectively,but without inhibitory effect on the activities of other P450 isoforms. So,drug-drug interaction induced by inhibition of CYP450 enzymes should be paid more attention when compound sophora injection is used intravenously for therapy.

关 键 词：斑蝥酸钠维生素B6 复方苦参 细胞色素P450酶 酶抑制 药物相互作用 肝微粒体 

分 类 号：R977.2[医药卫生—药品]