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

    來源: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中國科學(xué)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(yùn)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(jī)制,并研究因有機(jī)陰離子轉(zhuǎn)運(yùn)體OATP1B介導(dǎo)引起的潛在藥物相互作用DDI對甘草甜素的影響。實(shí)驗(yàn)方法:在細(xì)胞和囊泡水平上表征肝轉(zhuǎn)運(yùn)蛋白,并與大鼠轉(zhuǎn)運(yùn)體進(jìn)行比較,采用大鼠(大鼠為OATP1B2)的利福平(OATP1B抑制劑)抑制實(shí)驗(yàn)評估OATP1B2在甘草酸清除和藥動(dòng)學(xué)中的作用,采用整合了轉(zhuǎn)運(yùn)體介導(dǎo)的膽汁排泄的甘草酸的PBPK模型,并用該模型預(yù)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(yùn)體(對應(yīng)大鼠OATP1B2)將甘草酸從血液攝取進(jìn)入肝臟,人外排轉(zhuǎn)運(yùn)體MRP2、BCRP、BSEP、MDR-1(對應(yīng)大鼠MRP2/BCRP/BSEP)介導(dǎo)藥物外排進(jìn)入膽汁中。利福平(OATP1B抑制劑)將抑制大鼠肝臟攝取型轉(zhuǎn)運(yùn)體,導(dǎo)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?yàn)V過率較低。最終導(dǎo)致甘草酸體內(nèi)暴露量較高。PBPK模型的定量分析表明當(dāng)甘草酸與轉(zhuǎn)運(yùn)體抑制劑聯(lián)合給藥時(shí),甘草酸藥動(dòng)學(xué)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(fēng)險(xiǎn)。

    結(jié)論:

    轉(zhuǎn)運(yùn)體介導(dǎo)甘草酸的肝臟攝取與膽汁排泄,影響其消除與藥代動(dòng)力學(xué),定量分析OATP1B1/1B3轉(zhuǎn)運(yùn)體介導(dǎo)的甘草酸潛在DDI風(fēng)險(xiǎn),可以增強(qiáng)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.

    圓點(diǎn)代表不用利福平處理空白對照組大鼠,正方形點(diǎn)代表用利福平處理的大鼠,A和B圖代表大鼠靜脈注射2.6mg/kg 皂苷,血漿中甘草甜素和甘草酸-3-O-糖醛酸的濃度-時(shí)間曲線及對數(shù)圖

    A和B圖分別代表人靜脈滴注甘草甜素40mg(綠色線)、80mg(藍(lán)色線)、120mg(紅色線)后,血漿中甘草甜素的濃度時(shí)間曲線圖及對數(shù)圖

    下載該篇文章的英文原文獻(xiàn)PDF文件: 002.Glycyrrhizin-has-a-high-likelihood-to-be-a-victim-of-drug-drug-interactions-mediated-by-hepatic-OATP1B1_1B3.pdf (下載800)

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