抗乙肝候选新药替芬泰的体外转运机制研究
发布时间：2018-08-23 15:32
【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,有良好的抗乙肝病毒作用。在临床前药代动力学评价研究中发现灌胃给予大鼠Y101后,在大鼠体内的吸收、分布特征可能均与其跨膜转运有关联。本研究应用Caco-2细胞和基因转染细胞模型MDCK-MDR1,通过测定Y101的表观通透系数(P_(app))和外排率(R_E),研究Y101与P-gp的相互作用,结果表明Y101为P-gp的底物。此外,应用基因转染细胞模型HEK293-h OATP1B1、HEK293-h OATP2B1和CHO-PEPT1,探讨Y101与OATP1B1、OATP2B1和PEPT1转运体的亲和性,结果显示Y101对OATP1B1和OATP2B1两种转运体有弱的抑制作用,且Y101可能不是PEPT1、OATP1B1和OATP2B1的底物。上述结果不仅可以用来解释Y101给药后体内出现的吸收、分布特征,而且可以为Y101的进一步开发提供理论依据。
[Abstract]:As a class of phenylalanine dipeptide derivatives, tifentai (Y 101), a candidate anti-hepatitis B drug, has a good anti-HBV effect. In the study of preclinical pharmacokinetic evaluation, it was found that the absorption and distribution of Y101 in rats could be related to its transmembrane transport. In this study, the Caco-2 cell and gene transfected cell model MDCK-MDR1 were used to study the interaction between Y101 and P-gp by measuring the apparent permeability coefficient (P _ (app) and excretion rate (re) of Y101. The results showed that Y101 was the substrate of P-gp. In addition, the affinity of Y101 to OATP2B1 and OATP2B1 transporters was investigated by using gene transfected cell model HEK293-h OAT1B1HHEK293-h OATP2B1 and CHO-PEPT1. The results showed that Y101 had a weak inhibitory effect on OATP1B1 and OATP2B1 transporters, and Y101 might not be the substrate of PEPT1OAT1B1 and OATP2B1. The above results can not only explain the absorption and distribution of Y101, but also provide theoretical basis for the further development of Y101.
【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;贵州省中国科学院天然产物化学重点实验室;
【基金】：科技部国家科技重大专项课题(2011ZX09102-009-02) 贵州省中药现代化科技产业研究开发专项项目([2010]5018) 国家自然科学基金重点项目(81430096)
【分类号】：R965
本文编号：2199493
[Abstract]:As a class of phenylalanine dipeptide derivatives, tifentai (Y 101), a candidate anti-hepatitis B drug, has a good anti-HBV effect. In the study of preclinical pharmacokinetic evaluation, it was found that the absorption and distribution of Y101 in rats could be related to its transmembrane transport. In this study, the Caco-2 cell and gene transfected cell model MDCK-MDR1 were used to study the interaction between Y101 and P-gp by measuring the apparent permeability coefficient (P _ (app) and excretion rate (re) of Y101. The results showed that Y101 was the substrate of P-gp. In addition, the affinity of Y101 to OATP2B1 and OATP2B1 transporters was investigated by using gene transfected cell model HEK293-h OAT1B1HHEK293-h OATP2B1 and CHO-PEPT1. The results showed that Y101 had a weak inhibitory effect on OATP1B1 and OATP2B1 transporters, and Y101 might not be the substrate of PEPT1OAT1B1 and OATP2B1. The above results can not only explain the absorption and distribution of Y101, but also provide theoretical basis for the further development of Y101.
【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;贵州省中国科学院天然产物化学重点实验室;
【基金】：科技部国家科技重大专项课题(2011ZX09102-009-02) 贵州省中药现代化科技产业研究开发专项项目([2010]5018) 国家自然科学基金重点项目(81430096)
【分类号】：R965
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