HY152-J对人重组肝微粒体细胞色素P450亚型酶的体外抑制作用  

Inhibitory effect of HY152-J against artificial restructured human liver microsomal CYP450 enzymes in vitro

作　　者：冯有恒 王纪元 顾留歌 秦燕[1,2] 

机构地区：[1]中国医药工业研究总院上海医药工业研究院创新药物与制药工艺国家重点实验室,上海200437 [2]上海市生物物质成药性评价专业技术服务中心,上海200437

出　　处：《世界临床药物》2018年第2期130-134,共5页World Clinical Drug

基　　金：上海市科委"科技创新行动计划"生物医药领域科技支撑项目(编号:13431900203)

摘　　要：目的考察HY152-J对人重组肝微粒体细胞色素P450(CYP450)5种亚型酶活性的影响。方法利用不同浓度HY152-J与重组酶的体外孵育试验,以睾酮、咪达唑仑、美芬妥英、右美沙芬、非那西汀和双氯芬酸为CYP450酶探针底物,应用优化液相色谱-串联质谱(LC-MS/MS)法比较代谢产物(6β-羟基睾酮、1-羟基咪达唑仑、4-羟基美芬妥英、去甲右美沙芬、对乙酰氨基酚和4-羟基双氯芬酸)的量,计算半数抑制浓度(IC50)值,评价HY152-J对5种人CYP450亚型酶的抑制活性。结果在HY152-J浓度范围为0~200μmol/L的各孵育体系中,CYP3A4(6β-羟基睾酮)、CYP3A4(1-羟基咪达唑仑)、CYP2C19(4-羟基美芬妥英)、CYP2D6(去甲右美沙芬)、CYP1A2(对乙酰氨基酚)和CYP2C9(4-羟基双氯芬酸)的剩余活性百分比分别为4.6%、0.6%、0.3%、8.1%、32.5%和15.3%,对应IC50值分别为21.02、2.66、1.23、14.9、71.0和35.8μmol/L。结论 HY152-J对CYP3A4(1-羟基咪达唑仑)和CYP2C19具有中度抑制作用,对CYP3A4(6β-羟基睾酮)、CYP2D6、CYP1A2和CYP2C9抑制作用较弱。Objective To study the inhibitory effect of HY152-J against artificial restructured human liver microsomal CYP450 enzymes in vitro. Methods The method of single substrate CYP450 enzyme probe was used to study the inhibitory effect of HY152-J, and the metabolites of the precipitated samples for each probe were analyzed by LC-MS/MS. The concentration of metabolites was assayed to calculate the IC50 for inhibitory potency evaluation. Results The residual activities of CYP3A4（6β-hydroxytestosterone）, CYP3A4（1-hydroxymidazolam）, CYP2C19（4-hydroxymephenytoin）, CYP2D6（dextrophan）, CYP1A2（acetaminophen） and CYP2C9（4-hydroxydiclofenac） were analyzed as 4.6%, 0.6%, 0.3%, 8.1%, 32.5% and 15.3% respectively, and the IC50 values were 21.02, 2.66, 1.23,14.9, 71.0 and 35.8 μmol/L. Conclusion The inhibitory effects of HY152-J on CYP3A4（1-hydroxymidazolam）, CYP2C19 are moderate inhibition,and the effects on CYP3A4（6β-hydroxytestosterone）, CYP2D6, CYP1A2 and CYP2C9 are very few effections.

关 键 词：HY152-J 肝微粒体 细胞色素P450酶 优化液相色谱-串联质谱(LC-MS/MS) 

分 类 号：R521[医药卫生—内科学] R978.3[医药卫生—临床医学]