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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。
Anti-hepatitis B candidate new drug Tiftamate (Y101) is a class of phenylalanine dipeptide derivatives, has a good anti-hepatitis B virus effect. In preclinical pharmacokinetic evaluation studies, we found that the absorption and distribution of Y101 in rats may be related to its transmembrane transport. In this study, Caco-2 cells 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_application) and efflux rate (R_E) The results show that Y101 is a P-gp substrate. In addition, the gene-transfected cell models HEK293-h OATP1B1, HEK293-h OATP2B1 and CHO-PEPT1 were used to investigate the affinity of Y101 with OATP1B1, OATP2B1 and PEPT1 transporters. The results showed that Y101 had weak affinity to both OATP1B1 and OATP2B1 transporters And Y101 may not be a substrate for PEPT1, OATP1B1 and OATP2B1. The above results can not only be used to explain the absorption and distribution characteristics of Y101 in vivo, but also provide a theoretical basis for the further development of Y101.