Fan Hui-rong, Ci Xiao-yan, Li Wei, Dong Shi-qi, Zeng Yong, Yi Xiu-lin, Si Duan-yun, Liu Chang-xiao
Yao Xue Xue Bao. 2016 Dec;51(12):1864-70.
Bentysrepinine (Y101), a derivative of phenyalanine dipeptide, has a novel mechanism in the treatment of hepatitis B virus (HBV) infection with a good anti-HBV effect. In the present study, a fluorometric-based high throughput method using cytochrome P450 (CYP) screening kit was adopted to evaluate in vitro inhibition potential of Y101 on CYP isoenzymes by calculating remaining enzyme activities and inhibitory potential (IC(50) values) using the determined values of fluorescence intensity. The result showed that Y101 exhibited little activity in the inhibition of CYP1A2, CYP3A4, CYP2C9, CYP2C19 and CYP2D6 (IC(50) > 100 μmol·L(-1)). Y101 was used to treat human primary hepotocytes for 72 h, and the enzyme activities of CYP1A2, CYP2B6 and CYP3A4 were determined with a cocktail of probe substrates for the three CYP isoforms. The metabolites were simultaneously determined using a LC-MS/MS method. Y101 had no activity in the induction of CYP1A2, CYP2B6 and CYP3A4 on the basis of the following results: 1 The ratio of enzyme activities between test and control groups were all below than 1 (varied from 0.662 to 0.928); 2 The induction potential of Y101 were lower than forty percent compared with that of positive groups. The above results suggest that Y101 has little activity in the regulation of metabolic drug-drug interactions based on the CYP isoform changes following co-administration of drugs.
苯丙氨酸二肽衍生物本替斯瑞平（Y101）在治疗乙型肝炎病毒（HBV）感染方面具有新机制，抗HBV效果良好。在本研究中，采用基于荧光法的高通量方法，使用细胞色素P450（CYP）筛选试剂盒，通过计算剩余酶活性和抑制潜力（IC50值）（利用荧光强度测定值）来评估Y101对CYP同工酶的体外抑制潜力。结果表明，Y101对CYP1A2、CYP3A4、CYP2C9、CYP2C19和CYP2D6的抑制活性较低（IC50＞100μmol·L-1）。用Y101处理人原代肝细胞72小时，并用三种CYP同工型的探针底物混合物测定CYP1A2、CYP2B6和CYP3A4的酶活性。同时采用液相色谱-串联质谱法测定代谢产物。基于以下结果，Y101对CYP1A2、CYP2B6和CYP3A4无诱导活性：1. 试验组与对照组的酶活性比值均低于1（范围为0.662至0.928）；2. Y101的诱导潜力与阳性组相比低于40%。上述结果表明，基于药物联合使用后CYP同工型变化，Y101在调节药物代谢相互作用方面活性较低。
