Piperine enhances the bioavailability of silybin via inhibition of efflux transporters BCRP and MRP2
Piperine enhances the bioavailability of silybin via inhibition of efflux transporters BCRP and MRP2
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DOI：
10.1016/j.phymed.2018.09.217
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发表时间：
2019-02-15
期刊：
影响因子：
7.9
通讯作者：
Xie Ying
中科院分区：
文献类型：
--
作者：
Bi Xiaoli;Yuan Zhongwen;Xie Ying
背景：尽管水飞蓟宾具有显著的抗炎、抗氧化和抗纤维化活性，但其生物利用度低限制了其在慢性肝病治疗中的应用。假设/目的：我们假设抑制水飞蓟宾外排转运体(S)和/或胡椒碱的葡萄糖醛酸化作用可以提高水飞蓟宾的生物利用度和有效性。方法：采用LC-MS法测定水飞蓟宾单独给药或与胡椒碱合用后的药代动力学。建立CCl4诱导的大鼠肝损伤模型，比较水飞蓟宾和联合用药的效果。为了探讨胡椒碱对水飞蓟宾转运的抑制作用，我们在Caco-2细胞、MDCKII细胞系和夹心培养的大鼠肝细胞(SCH)上观察了胡椒碱对水飞蓟宾转运的抑制作用。结果：本研究首次证实了胡椒碱作为生物促进剂可提高水飞蓟宾的生物利用度(146%~181%)，从而增强了对CCl4所致急性肝损伤大鼠的治疗作用。其机制可能与胡椒碱通过抑制包括MRP2和BCRP在内的外排转运蛋白而不是通过抑制MDR1而促进水飞蓟宾在Caco-2和MDCKII细胞中的吸收。此外，胡椒碱还能抑制夹心培养的大鼠肝细胞胆汁中水飞蓟宾及其结合代谢产物的排泄。值得注意的是，我们发现胡椒碱不影响水飞蓟宾的2相代谢。结论：外排转运体在黄素木脂素的药代动力学行为中起着重要作用，用胡椒碱等生物增强剂调节这些转运体可以促进水飞蓟宾在体内的吸收，从而导致更有效的治疗。
Background: Although silybin serves as a well-known hepatoprotective agent with prominent anti-inflammatory, anti-oxidant and anti-fibrotic activities, its low bioavailability limits its application in the treatment of chronic liver diseases. However, novel formulation products with increased solubility were not sufficient to achieve pharmacologically meaningful concentrations of silybin in the clinical studies even used at high dosage.Hypothesis/Purpose: We hypothesized that inhibiting efflux transporter(s) and/or glucuronidation by piperine might enhance the bioavailability and efficacy of silybin.Methods: Pharmacokinetics of silybin given alone or in-combination with piperine was determined by a validated LC-MS method. A CCl4 induced rat model of liver injury was prepared and verified for comparing the effects of silybin and combination treatment. To investigate the underlying mechanism, the inhibition effects of piperine on transportation of silybin were performed in Caco-2 and transfected MDCKII cell lines as well as sandwich-cultured rat hepatocytes (SCH). Human liver microsomes incubation was used for exploring the modulation effects of piperine on the phase-2 metabolism of silybin.Results: In the present study, we demonstrated for the first time that piperine as a bioenhancer increased the bioavailability of silybin (146%- 181%), contributing to a boosted therapeutic effect in CCl4-induced acute liver-injury rat model. The underlying mechanisms involved that piperine enhanced the absorption of silybin by inhibiting the efflux transporters including MRP2 and BCRP but not MDR1 in Caco-2 and transfected MDCKII cell lines. Moreover, piperine could inhibit the biliary excretion of silybin and conjugated metabolites in sandwich-cultured rat hepatocytes. Notably, we found that piperine did not affect the phase-2 metabolism of silybin.Conclusion: Efflux transporters play an important role in the pharmacokinetic behavior of flavolignans, and modulating these transporters by bioenhancer such as piperine could enhance the in vivo absorption of silybin, leading to more effective treatments.