State Key Laboratory for Quality Research of Chinese Medicines, Macau University of Science and Technology, Taipa, Macau (SAR), China.
State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, 300193, China.
Pharmacol Res. 2018 Feb;128:153-166. doi: 10.1016/j.phrs.2017.09.019. Epub 2017 Sep 27.
Biological responses of a variety of naturally occurring compounds in vivo were restrained by their poor oral bioavailability. Silybin, as one of the active ingredients of silymarin, has presented promising bioactivity for the treatment of chronic liver diseases and cancer. However, its exposure in body was limited. In this study, silybin was demonstrated to be substrates of both BCRP and MRP2 by utilizing monolayer Caco-2 cell model and confirmed in MDCK cells overexpressing specific efflux transporter. Of all compounds screened, tangeretin, a potent inhibitor of efflux transporters of BCRP, MRP2 and P-gp, was able to enhance exposure of silybin by inhibiting functions of the barriers mediating transcellular transport. Moreover, study carried out in sandwich-cultured rat hepatocyte (SCH) model showed that the biliary excretion index (BEI) and in vitro biliary clearance of silybin decreased as levels of tangeretin increased, indicating efflux transporters mediating biliary excretion of silybin might be involved. Pharmacokinetic behaviors of silybin in rats were altered by co-administration of tangeretin, in terms of increased AUC and Cmax of silybin by comparing with that of silybin given alone. In addition, results coming from CCl-induced acute liver injury rat model revealed that protection effect of silybin against liver damage in the presence of tangeretin was significantly enhanced. All these data were evident that efflux transporters play a critical role in transcellular transport of silybin and account for its low bioavailability. Enhanced bioavailability of silybin with co-administration of tangeretin by significantly inhibiting the efflux transporters further boost its bioactivity which is of particular importance in clinical use.
生物体内多种天然存在的化合物的生物反应受到其口服生物利用度差的限制。水飞蓟宾作为水飞蓟素的一种活性成分，在治疗慢性肝病和癌症方面表现出了有前景的生物活性。然而，它在体内的暴露量有限。在本研究中，利用单层 Caco-2 细胞模型证实水飞蓟宾是 BCRP 和 MRP2 的底物，并在过表达特定外排转运体的 MDCK 细胞中得到了证实。在所筛选的所有化合物中，橙皮素是 BCRP、MRP2 和 P-糖蛋白的外排转运体的有效抑制剂，能够通过抑制介导细胞间转运的屏障功能来增加水飞蓟宾的暴露量。此外，在夹心培养大鼠肝细胞 (SCH) 模型中进行的研究表明，随着橙皮素水平的增加，水飞蓟宾的胆汁排泄指数 (BEI) 和体外胆汁清除率降低，表明参与水飞蓟宾胆汁排泄的外排转运体可能起作用。与单独给予水飞蓟宾相比，橙皮素共给药改变了水飞蓟宾在大鼠中的药代动力学行为，表现为水飞蓟宾的 AUC 和 Cmax 增加。此外，来自 CCl 诱导的急性肝损伤大鼠模型的结果表明，在橙皮素存在下，水飞蓟宾对肝损伤的保护作用显著增强。所有这些数据表明，外排转运体在水飞蓟宾的细胞间转运中起关键作用，是其低生物利用度的原因。橙皮素与水飞蓟宾共给药可显著抑制外排转运体，从而增强水飞蓟宾的生物利用度，这对临床应用尤为重要。
