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In Vitro Investigation of the Hepatobiliary Disposition Mechanisms of the Antifungal Agent Micafungin in Humans and Rats.
抗真菌药米卡芬净人类和大鼠肝胆处置机制的体外研究

出处: Drug Metab Dispos   2010   Jul  

作者:Yanni SB;Augustijns P;Benjamin DK;Brouwer KL;Thakker DR;Annaert PP

PMID:20606004

The purpose of the present study was to elucidate the transport mechanisms responsible for elimination of micafungin, a new semi-synthetic echinocandin antifungal agent, which is predominantly cleared by biliary excretion in humans and rats. In vitro studies using sandwich-cultured rat and human hepatocytes were conducted. Micafungin uptake occurred primarily (~75%) by transporter-mediated mechanisms in rat and human. Micafungin uptake into hepatocytes was inhibited by taurocholate (Ki = 61 muM), Na(+)-depletion (45-55% reduced), and by 10 muM rifampin (20-25% reduced): these observations support the involvement of Na(+)-taurocholate co-transporting polypeptide (NTCP, Ntcp) and, to a lesser extent, organic anion transporting polypeptides (OATP, Oatps) in the hepatic uptake of micafungin. The in vitro biliary clearance (Cl(biliary)) of micafungin, as measured by the B-CLEAR(R) technique, amounted to 14 muL/min/mg protein and 19 muL/min/mg protein in human and rat, respectively. In vitro biliary excretion of micafungin was reduced by 80 % and 75 % in the presence of the bile salt export pump (BSEP) inhibitors taurocholate (100 microM) and nefazodone (25 muM), respectively. Biliary excretion of micafungin also was reduced in the presence of breast cancer resistance protein (BCRP) inhibitors [GF120918 (10 muM) and fumitremorgin C (10 muM)]. In vitro biliary excretion of micafungin was not significantly altered by co-incubation with P-glycoprotein (P-gp) or multidrug resistance associated protein 2 (MRP2) inhibitors. These results suggest that NTCP/Ntcp and BSEP/Bsep are primarily responsible for hepatobiliary disposition of micafungin in human and rat. Interference with hepatic bile acid disposition could be one mechanism underlying hepatotoxicity associated with micafungin in some patients.

米卡芬净是一种新型半合成棘白菌素类抗真菌药物,在人类和大鼠主要经胆汁分泌而清除。本研究目的是阐明米卡芬净消除的转运机制。这项体外研究运用三明治构型培养大鼠和人类肝脏细胞。在大鼠和人类中,肝脏对米卡芬净的摄取主要由转运体介导的机制来完成(~75%)。肝细胞对米卡芬净的摄取可被牛磺胆酸盐(Ki = 61 muM)、Na(+)-耗竭 (减少45-55% )和10 muM 利福平 (减少20-25%)所抑制:这些结果表明Na(+)-牛磺胆酸盐共同转运多肽(Na(+)-taurocholate co-transporting polypeptide,NTCP或Ntcp)参与肝脏对米卡芬净的摄取,有机阴离子转运多肽类 (organic anion transporting polypeptides,OATP或Oatps) 在较小程度上也参与肝脏对米卡芬净的摄取。用 B-CLEAR(R)技术测定米卡芬净体外胆汁清除率 (biliary clearance,Cl(biliary)),在人类和大鼠中分别达14 muL/min/mg 蛋白和19 muL/min/mg 蛋白。在体外,胆盐输出泵 (bile salt export pump,BSEP)抑制剂牛磺胆酸盐(100 microM)和奈法唑酮 (25 muM)使米卡芬净的胆汁排泄分别减少了80 %和75%。乳腺癌耐药蛋白 (breast cancer resistance protein,BCRP)抑制剂[GF120918 (10 muM)和fumitremorgin C (10 muM)]也降低了米卡芬净的胆汁排泄。在体外,米卡芬净的胆汁排泄不会因与P-糖蛋白 (P-gp) 或多药耐药相关蛋白2 (multidrug resistance associated protein 2,MRP2) 抑制剂共同培养而发生明显改变。这些结果提示NTCP/Ntcp与BSEP/Bsep 主要负责人类和大鼠肝胆系统对米卡芬净的处置。干扰肝脏胆酸的处置可能是米卡芬净在一些患者中引起肝脏毒性反应的主要机制。