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 Dong1,2,Olajide E.Olaleye1, Rongrong Jiang1, Jing Li1,Chuang Lu3, Feifei Du1,Fang Xu1,Junling Yang1, Fengqing Wang1,Weiwei Jia1,Chuan Li1,2

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.

圆点代表不用利福平处理空白对照组大鼠,正方形点代表用利福平处理的大鼠,A和B图代表大鼠静脉注射2.6mg/kg 皂苷,血浆中甘草甜素和甘草酸-3-O-糖醛酸的浓度-时间曲线及对数图

A和B图分别代表人静脉滴注甘草甜素40mg(绿色线)、80mg(蓝色线)、120mg(红色线)后,血浆中甘草甜素的浓度时间曲线图及对数图

下载该篇文章的英文原文献PDF文件: 002.Glycyrrhizin-has-a-high-likelihood-to-be-a-victim-of-drug-drug-interactions-mediated-by-hepatic-OATP1B1_1B3.pdf (下载397)

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