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
藥物相互作用
結(jié)果:
人OATP1B1/1B3攝取轉(zhuǎn)運(yùn)體(對(duì)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(duì)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。
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(duì)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(duì)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(duì)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 (674 downloads)
您好!Please log in