甘草酸很有可能成为肝脏OATP1B1/1B3转运体介导的药物相互作用的“受害者”

来源：Br J Pharmacol. 2018 Jun 16.

原文作者

Jiajia Dong^1,2,Olajide E.Olaleye¹, Rongrong Jiang¹, Jing Li¹,Chuang Lu³, Feifei Du¹,Fang Xu¹,Junling Yang¹, Fengqing Wang¹,Weiwei Jia¹,Chuan Li^1,2

¹中国科学院上海药物研究所

²中科院

³赛诺菲公司，美国DMPK部门

翻译

何红梅凡默谷技术部

关键词

保肝甘草酸转运体胆汁排泄

药物相互作用

摘要

研究背景与目的：静脉注射甘草甜素，具有抗炎和保肝的作用；用于肝病的临床治疗，经常与其他药物联合使用。本次研究旨在阐明甘草甜素肝胆排泄的分子机制，并研究因有机阴离子转运体OATP1B介导引起的潜在药物相互作用DDI对甘草甜素的影响。实验方法：在细胞和囊泡水平上表征肝转运蛋白，并与大鼠转运体进行比较，采用大鼠（大鼠为OATP1B2）的利福平（OATP1B抑制剂）抑制实验评估OATP1B2在甘草酸清除和药动学中的作用，采用整合了转运体介导的胆汁排泄的甘草酸的PBPK模型，并用该模型预测了人体内甘草酸的潜在药物相互作用。

结果：

人OATP1B1/1B3摄取转运体（对应大鼠OATP1B2）将甘草酸从血液摄取进入肝脏，人外排转运体MRP2、BCRP、BSEP、MDR-1（对应大鼠MRP2/BCRP/BSEP）介导药物外排进入胆汁中。利福平（OATP1B抑制剂）将抑制大鼠肝脏摄取型转运体，导致甘草酸的系统暴露量明显增加；此外，甘草酸与血浆蛋白广泛结合，其肾小球滤过率较低。最终导致甘草酸体内暴露量较高。PBPK模型的定量分析表明当甘草酸与转运体抑制剂联合给药时，甘草酸药动学过程中发挥关键作用的OATP1B1/1B3将受到抑制，并引起潜在的药物相互作用DDI风险。

结论：

转运体介导甘草酸的肝脏摄取与胆汁排泄，影响其消除与药代动力学，定量分析OATP1B1/1B3转运体介导的甘草酸潜在DDI风险，可以增强甘草酸与其他药物合用治疗肝脏疾病的成功率。

Abstract

BACKGROUND AND PURPOSEIntravenous glycyrrhizin, having anti-inflammatory and hepatoprotective properties, is incorporated intothemanagement of liver diseases in China. This investigation was designed toelucidatethemolecular mechanism underlying hepatobiliary excretion of glycyrrhizin and toinvestigateits potentialfordrug-druginteractions on organic anion-transporting polypeptides (OATP)1B.EXPERIMENTAL APPROACHHuman hepatic transporters were characterized forglycyrrhizin at the cellular and vesicular levelsand compared with rat hepatic transporters. A rifampin-based inhibition study in rats evaluated the role of Oatp1b2in glycyrrhizin’selimination andpharmacokinetics.Aphysiologically-based pharmacokinetic(PBPK)modelfor glycyrrhizin,incorporating transporter-mediated hepatobiliary excretion,was established and applied to predicting potential drug-drug interactions relating to glycyrrhizinin humans.

KEY RESULTS

Hepatobiliary excretion of glycyrrhizin involved human OATP1B1/1B3-(orOatp1b2inrats)mediated hepatic uptake from blood and human multidrug resistance-associated protein (MRP)2/breast cancer resistance protein (BCRP)/bile salt export pump (BSEP)/multidrug resistance protein(MDR)1-(orMrp2/Bcrp/Bsepin rats)mediatedhepaticefflux into bile. Impairment of hepatic uptakein rats by rifampin resulted insignificantly increased systemic exposure to glycyrrhizin, which had slow glomerular-filtration-based renal excretion due to extensive protein-binding in plasma. Quantitative analysis using the PBPK model demonstrated the critical roles of OATP1B1/1B3 in pharmacokinetics ofglycyrrhizin,which hadhigh likelihoodto be avictimof drug-drug interactions when coadministered with potent dual inhibitors of these transporters.

CONCLUSION AND IMPLICATIONS

Transporter-mediated hepatobiliary excretion governs glycyrrhizin’selimination and pharmacokinetics. Understanding glycyrrhizin’s potential drug-drug interactions on OATP1B1/1B3 is expected to enhance success of glycyrrhizin-including combination drug therapies of liver diseases.