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    甘草酸很有可能成為肝臟OATP1B1/1B3轉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 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? 凡默谷技術部
    關鍵詞
    保肝甘草酸轉運體膽汁排泄

    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,經常與其他藥物聯合使用。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運蛋白,并與大鼠轉運體進行比較,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甘草酸的潛在藥物相互作用。

    結果:

    人OATP1B1/1B3攝取轉運體(對應大鼠OATP1B2)將甘草酸從血液攝取進入肝臟,人外排轉運體MRP2、BCRP、BSEP、MDR-1(對應大鼠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運體,導致甘草酸的系統暴露量明顯增加;此外,甘草酸與血漿蛋白廣泛結合,其腎小球濾過率較低。最終導致甘草酸體內暴露量較高。PBPK模型的定量分析表明當甘草酸與轉運體抑制劑聯合給藥時,甘草酸藥動學過程中發揮關鍵作用的OATP1B1/1B3將受到抑制,并引起潛在的藥物相互作用DDI風險。

    結論:

    轉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.

    圓點代表不用利福平處理空白對照組大鼠,正方形點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-時間曲線及對數圖

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

    下載該篇文章的英文原文獻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287)

    標簽:OATP1B1/1B3轉運體介導甘草酸肝臟OATP1B1/1B3轉運體介導藥物相互作用 上一篇: 下一篇:

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