亚投彩票

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赛诺菲亚投彩票,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

YAOWUXIANGHUZUOYONG

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:

RENOATP1B1/1B3SHEQUZHUANYUNTI(DUIYINGDASHUOATP1B2)JIANGGANCAOSUANCONGXUEYESHEQUJINRUGANZANG,RENWAIPAIZHUANYUNTIMRP2、BCRP、BSEP、MDR-1(DUIYINGDASHUMRP2/BCRP/BSEP)JIEDAOYAOWUWAIPAIJINRUDANZHIZHONG。LIFUPING(OATP1BYIZHIJI)JIANGYIZHIDASHUGANZANGSHEQUXINGZHUANYUNTI,DAOZHIGANCAOSUANDEXITONGBAOLULIANGMINGXIANZENGJIA;CIWAI,GANCAOSUANYUXUEJIANGDANBAIGUANGFANJIEHE,QISHENXIAOQIULVGUOLVJIAODI。ZUIZHONGDAOZHIGANCAOSUANTINEIBAOLULIANGJIAOGAO。PBPKMOXINGDEDINGLIANGFENXIBIAOMINGDANGGANCAOSUANYUZHUANYUNTIYIZHIJILIANHEJIYAOSHI,GANCAOSUANYAODONGXUEGUOCHENGZHONGFAHUIGUANJIANZUOYONGDEOATP1B1/1B3JIANGSHOUDAOYIZHI,BINGYINQIQIANZAIDEYAOWUXIANGHUZUOYONGDDIFENGXIAN。

结论:

ZHUANYUNTIJIEDAOGANCAOSUANDEGANZANGSHEQUYUDANZHIPAIXIE,YINGXIANGQIXIAOCHUYUYAODAIDONGLIXUE,DINGLIANGFENXIOATP1B1/1B3ZHUANYUNTIJIEDAODEGANCAOSUANQIANZAIDDIFENGXIAN,KEYIZENGQIANGGANCAOSUANYUQITAYAOWUHEYONGZHILIAOGANZANGJIBINGDECHENGGONGLV。

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

XIAZAIGAIPIANWENZHANGDEYINGWENYUANWENXIANPDFWENJIAN:[download id=”308″]

上一篇: 下一篇:

您好!请登录

点击取消回复
    展开更多

    loading...