抗乙肝候选新药替芬泰的体外转运机制研究  

The in vitro transport mechanism of bentysrepinine: a novel anti-hepatitis B virus drug candidate

作　　者：樊慧蓉[1] 慈小燕[2] 李薇[2] 曾勇[2] 伊秀林[2] 司端运[2] 刘昌孝[2] 梁光义[3] 

机构地区：[1]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300192 [2]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300193 [3]贵州省中国科学院天然产物化学重点实验室,贵州贵阳550002

出　　处：《药学学报》2016年第8期1233-1239,共7页Acta Pharmaceutica Sinica

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)

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。Bentysrepinine（Y101）, a derivative of phenylalanine dipeptide, is a novel drug candidate for the treatment of hepatitis B virus（HBV） infection. Our previous preclinical pharmacokinetic study showed that its in vivo absorption and distribution characteristics were probably related to transmembrane transport after Y101 was administered intragastically in rats. In this study, Caco-2 and MDCK-MDR1 cell models were used to investigate interactions between Y101 and P-gp through the apparent permeation coefficient（P_（app）） and efflux ratio（R_E）; the results showed that Y101 was a substrate of P-gp. In addition, gene-transfected cell models, HEK293-h OATP1B1, HEK293-h OATP2B1 and CHO-PEPT1 were used to evaluate the affinity to OATP1B1, OATP2B1 and PEPT1. The results suggest that Y101 has a weak inhibitory effect on OATP1B1 and OATP2B1, and Y101 may not be substrates of OATP1B1, OATP2B1 or PEPT1. The above results can be used to explain the in vivo absorption and distribution characteristics, and to provide a scientific basis for the further development of Y101.

关 键 词：替芬泰 体外转运机制 基因转染细胞 MDCK-MDR1 HEK293-hOATP1B1 HEK293-hOATP2B1 CHO-PEPT1 

分 类 号：R969[医药卫生—药理学]