参与抗癌新药F318体外代谢的大鼠细胞色素P450酶  

Characterization of rat cytochrome P450 enzymes involved in the in vitro metabolism of anticancer drug F318

作　　者：和凡[1] 苏启表[1] 赵立子[1] 卢宇靖[2] 古练权[2] 黄民[1] 

机构地区：[1]中山大学药学院临床药理研究所,广州510080 [2]中山大学药学院药物化学研究所,广州510275

出　　处：《中国新药杂志》2007年第10期765-769,共5页Chinese Journal of New Drugs

摘　　要：目的:体外研究大鼠肝微粒体中F318代谢的酶促动力学．及利用选择性细胞色素(CYP)酶抑制剂明确参与F318代谢的CYP亚型。方法:优化F318在大鼠肝微粒体中孵育的条件,并进行酶促动力学研究;探讨CYP酶的选择性抑制剂α-萘磺酮(CYP1A2),磺胺苯吡唑(CYP2C9),噻氯匹定(CYP2C19),查尼丁(CYP2D6),4-甲基吡唑(CYP2E1),酮康唑(CYP3A1)对其代谢的影响及参与其代谢的CYP亚型。结果:F318代谢的酶促动力学参数:最大反应速率(V_(max))为(1．40±0．03)μmol·min^(-1)·mg^(-1),米氏常数(K_m)为(19．36±2．30)μmol·L^(-1)。酮康唑可以显著地抑制F318代谢(抑制效果≈70％),而其他CYP特异性抑制剂对F318的代谢没有明显的影响。结论: CYP3A1主要参与了F318的代谢,CYP1A2,2C19和2D6也起到了部分代谢作用。Objective： To study the enzyme kinetics of F318 metabolism and the effects of selective CYP450 inhibitors on the metabolism of F318 in rat liver microsomes. Methods： An optimal incubation of F318 in rat liver microsomes and the related enzyme kinetic studies were investigated. A few of selective CYP inhibitors and CYP subtypes, including ct-naphthoflavone （α-NF, CYP1A2）, sulpha- phenazole （Sul, CYP2C9） , ticlopidine （Tic, CYP2C19） , quinidine （Quin, CYP2D6） , 4-methyl- pyrazole （4-MP, CYP2E1） , ketoconazole （Ket, CYP3A1 ） , and their correlation with the inhibition of F318 metabolism were assessed. Results： The enzyme kinetics parameter was Vmax = （1. 40± 0. 03） /μmol·min^-l·mg^-l, Km = （19.36±2.30）/μmol· L^-l. Ketoeonazole was the sole significant inhibitor of F318 metabolism in the selective inhibitors studied, manifesting an inhibition rate of 70%. Conclusion： CYP3A1 was the major enzyme involved in the F318 metabolism, and CYP1A2, CYP2C19, CYP2D6 partially contributed to the metabolism to some extent.

关 键 词：F318 肝微粒体 CYP450 酶促动力学 选择性抑制剂 

分 类 号：R979.1[医药卫生—药品] R965.2[医药卫生—药学]