Department of Pharmaceutical Sciences, Katholieke Universiteit Leuven, O&N2, Herestraat 49, Leuven, Belgium.
Drug Metab Dispos. 2010 Oct;38(10):1848-56. doi: 10.1124/dmd.110.033811. Epub 2010 Jul 6.
The purpose of the present study was to elucidate the transport mechanisms responsible for elimination of micafungin, a new semisynthetic 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 (K(i) = 61 μM), Na(+) depletion (45-55% reduced), and 10 μM rifampin (20-25% reduced); these observations support the involvement of Na(+)-taurocholate-cotransporting polypeptide (NTCP/Ntcp) and, to a lesser extent, organic anion-transporting polypeptides in the hepatic uptake of micafungin. The in vitro biliary clearance of micafungin, as measured by the B-CLEAR technique, amounted to 14 and 19 μl/(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 μM) and nefazodone (25 μM), respectively. Biliary excretion of micafungin also was reduced in the presence of breast cancer resistance protein inhibitors [N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918) (10 μM) and fumitremorgin C (10 μM)]. In vitro biliary excretion of micafungin was not significantly altered by coincubation with P-glycoprotein or multidrug resistance-associated protein 2 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.
本研究的目的在于阐明米卡芬净（一种新型半合成棘白菌素类抗真菌药物）的消除转运机制，米卡芬净在人体和大鼠中主要通过胆汁排泄清除。采用夹心培养的大鼠和人肝细胞进行体外研究。米卡芬净摄取主要通过大鼠和人中的转运体介导机制（约 75%）。米卡芬净进入肝细胞的摄取被牛磺胆酸钠（K(i) = 61 μM）、Na+耗竭（45-55%减少）和 10 μM 利福平（20-25%减少）抑制；这些观察结果支持 Na+-牛磺胆酸钠共转运蛋白（NTCP/Ntcp）和在较小程度上有机阴离子转运蛋白参与米卡芬净的肝摄取。通过 B-CLEAR 技术测量，米卡芬净的体外胆汁清除率在人体和大鼠中分别为 14 和 19 μl/（min·mg 蛋白）。在胆汁盐输出泵（BSEP）抑制剂牛磺胆酸钠（100 μM）和奈法唑酮（25 μM）存在的情况下，米卡芬净的体外胆汁排泄分别减少 80%和 75%。乳腺癌耐药蛋白抑制剂[N-（4-[2-（1,2,3,4-四氢-6,7-二甲氧基-2-异喹啉基）乙基]-苯基）-9,10-二氢-5-甲氧基-9-氧代-4-吖啶羧酸酰胺（GF120918）（10 μM）和呋塞米特隆 C（10 μM）]也降低了米卡芬净的胆汁排泄。米卡芬净的体外胆汁排泄与 P-糖蛋白或多药耐药相关蛋白 2 抑制剂共同孵育时无明显变化。这些结果表明，NTCP/Ntcp 和 BSEP/Bsep 主要负责米卡芬净在人体和大鼠中的肝胆处置。干扰肝胆汁酸处置可能是米卡芬净在某些患者中引起肝毒性的一种机制。
