抗乙肝候选新药替芬泰对细胞色素P450酶的体外抑制和诱导作用研究

发布时间：2018-12-13 18:06

【摘要】：抗乙肝候选新药替芬泰(Y101)是一类苯丙氨酸二肽衍生物,有全新的抗乙肝病毒机制和良好的抗乙肝病毒作用。本文应用基于荧光测定的高通量细胞色素P450酶(cytochrome P450,CYP)抑制筛选试剂盒,通过测定所得的荧光强度值,计算剩余酶活性及半数抑制浓度(IC50),评估Y101对CYP同工酶的抑制潜能,结果表明Y101对CYP1A2、CYP3A4、CYP2C9、CYP2C19和CYP2D6产生抑制作用的可能性较小(IC_(50)均大于100μmol·L~(-1))。人原代培养肝细胞中加入Y101培养72 h,以"Cocktail"法混合加入CYP1A2、CYP2B6和CYP3A4的探针底物进行反应,液相色谱-质谱联用(LC-MS/MS)法同时测定上述探针底物经CYP同工酶代谢的代谢产物浓度,计算CYP同工酶的剩余酶活性。实验组与空白对照组相比的酶活性比值均小于1(在0.662~0.928之间),与阳性对照组相比均小于其诱导能力的40%,结果表明Y101对CYP1A2、CYP2B6和CYP3A4无诱导潜能。结果表明,Y101可能不会在联合用药的过程中发生基于CYP酶抑制或诱导的代谢性相互作用。
[Abstract]:Tifentai (Y101) is a class of phenylalanine dipeptide derivatives, which has a new anti-HBV mechanism and a good anti-HBV effect. High throughput cytochrome P450 enzyme (cytochrome P450 CYP) inhibition screening kit based on fluorescence assay was used to calculate the residual enzyme activity and half inhibitory concentration (IC50). The inhibitory potential of Y101 on CYP isozyme was evaluated. The results showed that Y101 was less likely to inhibit CYP1A2,CYP3A4,CYP2C9,CYP2C19 and CYP2D6 (IC_ (50) > 100 渭 mol L ~ (-1). In primary culture of human hepatocytes, Y101 was added for 72 h, and the probe substrates of CYP1A2,CYP2B6 and CYP3A4 were mixed with "Cocktail" method for the reaction. The concentrations of metabolites metabolized by CYP isozyme were determined by liquid chromatography-mass spectrometry (LC-MS/MS), and the residual enzyme activity of CYP isozyme was calculated. Compared with the blank control group, the ratio of enzyme activity in the experimental group and the blank control group was less than 1 (in the range of 0.6620.928) and less than 40% of the inducing ability of the positive control group. The results showed that Y101 had no inductive potential on CYP1A2,CYP2B6 and CYP3A4. The results showed that Y101 might not have metabolic interaction based on inhibition or induction of CYP enzyme during the course of combined administration.
【作者单位】：中国医学科学院北京协和医学院放射医学研究所天津市放射医学与分子核医学重点实验室;天津药物研究院释药技术与药代动力学国家重点实验室;天津大学;
【基金】：科技部国家科技重大专项课题资助项目(2011ZX09102-009-02) 国家自然科学基金重点项目(81430096;81302870) 国家科技重大专项资助项目(2012ZX09506001-006) 贵州省中药现代化科技产业研究开发专项项目([2010]5018)
【分类号】：R96

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