Table_1_Baicalein Enhances the Oral Bioavailability and Hepatoprotective Effects of Silybin Through the Inhibition of Efflux Transporters BCRP and MRP2.PDF

Although hepatoprotective properties of silybin are well documented, the clinical therapeutic efficacy is limited by its low bioavailability due to absorption rates, extensive phase II metabolism, and biliary excretion. As our previous study indicated that metabolic enzymes may have limited effects on the pharmacokinetic (PK) behavior of silymarin, here, we intended to increase the oral bioavailability and bio-efficacy of silybin through the inhibition of active efflux. In Caco-2 and transfected MDCKII cell models, flavone baicalein significantly inhibited the efflux of silybin as a BCRP and MRP2 inhibitor. In addition, baicalein reduced the biliary excretion index (BEI) and biliary clearance of silybin conjugates in the sandwich-cultured rat hepatocyte (SCH) model, indicating the inhibition of baicalein in biliary excretion of conjugated silybin metabolites. PK study demonstrated that baicalein significantly increased the area under the curve (AUC) and Cmax of silybin and its conjugates, suggesting enhanced absorption in vivo. Moreover, coadministration of silybin with baicalein boosted the liver protective, antioxidant, and anti-inflammatory effects of silybin in the carbon tetrachloride (CCl4)-induced liver injury model in comparison with silybin given alone. In summary, efflux transporters play a critical role in the low bioavailability of silybin, while inhibition of breast cancer resistance protein (BCRP) and multi-drug resistance protein 2 (MRP2) by baicalein can significantly increase the absorption and bio-efficacy of silybin, which provides a new combination therapeutic approach for the treatment of chronic liver diseases.

尽管水飞蓟宾（silybin）的肝保护特性已有充分文献记载，但其临床治疗疗效因吸收速率、广泛的II相代谢及胆汁排泄导致的低生物利用度而受到限制。
我们先前的研究表明，代谢酶对水飞蓟素（silymarin）的药代动力学（pharmacokinetic, PK）行为影响有限，因此本研究旨在通过抑制主动外排过程，提升水飞蓟宾的口服生物利用度与生物药效。
在Caco-2细胞与转染MDCKII细胞模型中，黄酮类化合物黄芩素（baicalein）可作为乳腺癌耐药蛋白（BCRP）与多药耐药相关蛋白2（MRP2）抑制剂，显著抑制水飞蓟宾的外排作用。
此外，在三明治培养大鼠肝细胞（sandwich-cultured rat hepatocyte, SCH）模型中，黄芩素可降低水飞蓟宾结合物的胆汁排泄指数（biliary excretion index, BEI）与胆汁清除率，证实其可抑制结合型水飞蓟宾代谢物的胆汁排泄。
药代动力学研究结果显示，黄芩素可显著提升水飞蓟宾及其结合物的血药浓度-时间曲线下面积（area under the curve, AUC）与峰浓度（Cmax），提示其在体内可增强水飞蓟宾的吸收。
与单独给药的水飞蓟宾相比，在四氯化碳（carbon tetrachloride, CCl4）诱导的肝损伤模型中，水飞蓟宾与黄芩素联合给药可强化水飞蓟宾的肝保护、抗氧化与抗炎功效。
综上，外排转运蛋白在水飞蓟宾的低生物利用度中发挥关键作用，而黄芩素对BCRP与MRP2的抑制可显著提升水飞蓟宾的吸收与生物药效，为慢性肝脏疾病的治疗提供了全新的联合治疗策略。