Pharmacokinetic study of the hepatobiliary transport of indomethacin
Pharmacokinetic study of the hepatobiliary transport of indomethacin
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DOI：
10.1023/a:1007576903935
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发表时间：
2000-04-01
影响因子：
3.7
通讯作者：
Sugiyama, Y
中科院分区：
文献类型：
--
作者：
Kouzuki, H;Suzuki, H;Sugiyama, Y
目的.吲哚美辛及其葡糖苷酸的胆汁排泄量与其肠道毒性有关。在本研究中，我们研究了吲哚美辛的肝胆转运。本文研究了原代培养的大鼠肝细胞和转染牛磺胆酸钠共转运多肽和有机阴离子转运多肽1的COS-7细胞对吲哚美辛的摄取。此外，我们还比较了SD大鼠和遗传性小管多特异性有机阴离子转运蛋白/多药耐药相关蛋白2（cMOAT/MRP 2）功能缺陷的高胆红素血症大鼠（EHBR）的吲哚美辛及其葡萄糖醛酸苷的胆汁排泄。吲哚美辛进入大鼠肝细胞的摄取介导的NAT依赖性和独立的主动运输系统。两种转染子都不能刺激吲哚美辛的摄取。SD大鼠静脉滴注吲哚美辛后，胆汁排泄吲哚美辛葡萄糖醛酸苷超过吲哚美辛。SD大鼠和EHBR大鼠的消炎痛跨胆管膜转运清除率相当，而EHBR中消炎痛葡糖苷酸的相应值约为SD大鼠的50%。这些结果表明，另一种转运蛋白参与了吲哚美辛的肝摄取，吲哚美辛葡萄糖醛酸苷的小管转运由cMOAT/MRP 2介导，而吲哚美辛的小管转运不由cMOAT/MRP 2介导。
Purpose. The biliary excreted amount of indomethacin and its glucuronide is related to the intestinal toxicity of this drug. In the present study, we investigated the hepatobiliary transport of indomethacin.Methods. The uptake of indomethacin into primary cultured rat hepatocytes and COS-7 cells transfected with cDNA encoding sodium taurocholate co-transporting polypeptide or organic anion transporting polypeptide 1 was examined. Moreover, we compared the biliary excretion of indomethacin and its glucuronide between Sprague-Dawley (SD) rats and Eisai hyperbilirubinemic rats (EHBR) whose canalicular multispecific organic anion transporter/multidrug resistance associated protein 2 (cMOAT/MRP2) function is hereditarily defective.Results. The uptake of indomethacin into rat hepatocytes was mediated by Nat-dependent and independent active transport systems. Neither transfectant stimulated the uptake of indomethacin. After intravenous infusion of indomethacin to SD rats, the biliary excretion of indomethacin glucuronide exceeded that of indomethacin. The indomethacin transport clearance across the bile canalicular membrane was comparable between SD rats and EHBR, whereas the corresponding value for indomethacin glucuronide in EHBR was approximately 50% that in SD rats.Conclusions. These results indicate that another transporter(s) is involved in the hepatic uptake of indomethacin and the canalicular transport of indomethacin glucuronide is mediated by cMOAT/MRP2 whereas that of indomethacin is not mediated by cMOAT/MRP2.