甘草酸很有可能成為肝臟OATP1B1/1B3轉(zhuǎn)運體介導的藥物相互作用的“受害者”

來源：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中國科學院上海藥物研究所

²中科院

³賽諾菲公司，美國DMPK部門

翻譯

何紅梅? 凡默谷技術(shù)部

關(guān)鍵詞

保肝甘草酸轉(zhuǎn)運體膽汁排泄

藥物相互作用

摘要

研究背景與目的：靜脈注射甘草甜素，具有抗炎和保肝的作用；用于肝病的臨床治療，經(jīng)常與其他藥物聯(lián)合使用。本次研究旨在闡明甘草甜素肝膽排泄的分子機制，并研究因有機陰離子轉(zhuǎn)運體OATP1B介導引起的潛在藥物相互作用DDI對甘草甜素的影響。實驗方法：在細胞和囊泡水平上表征肝轉(zhuǎn)運蛋白，并與大鼠轉(zhuǎn)運體進行比較，采用大鼠（大鼠為OATP1B2）的利福平（OATP1B抑制劑）抑制實驗評估OATP1B2在甘草酸清除和藥動學中的作用，采用整合了轉(zhuǎn)運體介導的膽汁排泄的甘草酸的PBPK模型，并用該模型預測了人體內(nèi)甘草酸的潛在藥物相互作用。

結(jié)果：

人OATP1B1/1B3攝取轉(zhuǎn)運體（對應(yīng)大鼠OATP1B2）將甘草酸從血液攝取進入肝臟，人外排轉(zhuǎn)運體MRP2、BCRP、BSEP、MDR-1（對應(yīng)大鼠MRP2/BCRP/BSEP）介導藥物外排進入膽汁中。利福平（OATP1B抑制劑）將抑制大鼠肝臟攝取型轉(zhuǎn)運體，導致甘草酸的系統(tǒng)暴露量明顯增加；此外，甘草酸與血漿蛋白廣泛結(jié)合，其腎小球濾過率較低。最終導致甘草酸體內(nèi)暴露量較高。PBPK模型的定量分析表明當甘草酸與轉(zhuǎn)運體抑制劑聯(lián)合給藥時，甘草酸藥動學過程中發(fā)揮關(guān)鍵作用的OATP1B1/1B3將受到抑制，并引起潛在的藥物相互作用DDI風險。

結(jié)論：

轉(zhuǎn)運體介導甘草酸的肝臟攝取與膽汁排泄，影響其消除與藥代動力學，定量分析OATP1B1/1B3轉(zhuǎn)運體介導的甘草酸潛在DDI風險，可以增強甘草酸與其他藥物合用治療肝臟疾病的成功率。

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.