甘草(cǎo)酸很有可(kě)能成爲肝髒OATP1B1/1B3轉運體介導的(de)藥物(wù)相互作用(yòng)的(de)“受害者”

來(lái)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(wù)研究所

²中科院

³賽諾菲公司，美(měi)國DMPK部門

翻譯

何紅梅凡默谷技術部

關鍵詞

保肝甘草(cǎo)酸轉運體膽汁排洩

藥物(wù)相互作用(yòng)

摘要

研究背景與目的(de)：靜脈注射甘草(cǎo)甜素，具有抗炎和(hé)保肝的(de)作用(yòng)；用(yòng)于肝病的(de)臨床治療，經常與其他(tā)藥物(wù)聯合使用(yòng)。本次研究旨在闡明(míng)甘草(cǎo)甜素肝膽排洩的(de)分(fēn)子機制，并研究因有機陰離子轉運體OATP1B介導引起的(de)潛在藥物(wù)相互作用(yòng)DDI對(duì)甘草(cǎo)甜素的(de)影(yǐng)響。實驗方法：在細胞和(hé)囊泡水(shuǐ)平上表征肝轉運蛋白，并與大(dà)鼠轉運體進行比較，采用(yòng)大(dà)鼠（大(dà)鼠爲OATP1B2）的(de)利福平（OATP1B抑制劑）抑制實驗評估OATP1B2在甘草(cǎo)酸清除和(hé)藥動學中的(de)作用(yòng)，采用(yòng)整合了(le)轉運體介導的(de)膽汁排洩的(de)甘草(cǎo)酸的(de)PBPK模型，并用(yòng)該模型預測了(le)人(rén)體内甘草(cǎo)酸的(de)潛在藥物(wù)相互作用(yòng)。

結果：

人(rén)OATP1B1/1B3攝取轉運體（對(duì)應大(dà)鼠OATP1B2）将甘草(cǎo)酸從血液攝取進入肝髒，人(rén)外排轉運體MRP2、BCRP、BSEP、MDR-1（對(duì)應大(dà)鼠MRP2/BCRP/BSEP）介導藥物(wù)外排進入膽汁中。利福平（OATP1B抑制劑）将抑制大(dà)鼠肝髒攝取型轉運體，導緻甘草(cǎo)酸的(de)系統暴露量明(míng)顯增加；此外，甘草(cǎo)酸與血漿蛋白廣泛結合，其腎小球濾過率較低。最終導緻甘草(cǎo)酸體内暴露量較高(gāo)。PBPK模型的(de)定量分(fēn)析表明(míng)當甘草(cǎo)酸與轉運體抑制劑聯合給藥時(shí)，甘草(cǎo)酸藥動學過程中發揮關鍵作用(yòng)的(de)OATP1B1/1B3将受到抑制，并引起潛在的(de)藥物(wù)相互作用(yòng)DDI風險。

結論：

轉運體介導甘草(cǎo)酸的(de)肝髒攝取與膽汁排洩，影(yǐng)響其消除與藥代動力學，定量分(fēn)析OATP1B1/1B3轉運體介導的(de)甘草(cǎo)酸潛在DDI風險，可(kě)以增強甘草(cǎo)酸與其他(tā)藥物(wù)合用(yòng)治療肝髒疾病的(de)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.

圓點代表不用(yòng)利福平處理(lǐ)空白對(duì)照(zhào)組大(dà)鼠，正方形點代表用(yòng)利福平處理(lǐ)的(de)大(dà)鼠，A和(hé)B圖代表大(dà)鼠靜脈注射2.6mg/kg 皂苷，血漿中甘草(cǎo)甜素和(hé)甘草(cǎo)酸-3-O-糖醛酸的(de)濃度-時(shí)間曲線及對(duì)數圖