Involvement of multiple transporters in the hepatobiliary transport of rosuvastatin
Involvement of multiple transporters in the hepatobiliary transport of rosuvastatin
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DOI：
10.1124/dmd.108.021410
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发表时间：
2008-10-01
影响因子：
3.9
通讯作者：
Sugiyama, Yuichi
中科院分区：
文献类型：
--
作者：
Kitamura, Satoshi;Maeda, Kazuya;Sugiyama, Yuichi
瑞舒伐他汀是一种HMG-CoA还原酶抑制剂，是市售他汀类药物中亲水性最强的药物之一。在大鼠中，它在肝脏中有效蓄积，并以原形排泄到胆汁中，表明肝脏转运蛋白在其清除中起主要作用。因此，我们研究了负责瑞舒伐他汀肝脏摄取和胆汁排泄的转运蛋白。摄取研究表明，人有机阴离子转运多肽（OATP）1B 1、OATP 1B 3和OATP 2B 1接受瑞舒伐他汀作为底物。在OATP家族转运蛋白中，OATP 1B 1主要参与瑞舒伐他汀的肝脏摄取，如先前发表的相对活性因子方法所估计，OATP 1B 3也部分参与。与OATP 1B 1单转染细胞或载体转染对照细胞相比，在OATP 1B 1/多药耐药相关蛋白2（MRP 2）、OATP 1B 1/多药耐药蛋白1（MDR 1）和OATP 1B 1/乳腺癌耐药蛋白（BCRP）双转染细胞中观察到显著的载体基底至顶端转运。人BCRP表达膜囊泡对瑞舒伐他汀的ATP依赖性摄取显著高于绿色荧光蛋白表达对照囊泡的摄取，表明MRP 2、MDR 1和BCRP可转运瑞舒伐他汀。在体内条件下，基于原型药物瑞舒伐他汀肝内浓度，在高胆红素血症大鼠和Bcrp 1敲除小鼠中的胆汁排泄清除率分别降低至对照Sprague-道利大鼠和FVB小鼠的53%和12%，表明大鼠Mrp 2和小鼠Bcrp 1均部分参与瑞舒伐他汀的胆汁排泄。这些结果表明，多种转运蛋白参与了瑞舒伐他汀的肝脏摄取和外排。
Rosuvastatin is an HMG-CoA reductase inhibitor and one of the most hydrophilic among the commercially available statins. It is efficiently accumulated in the liver and excreted into the bile in an unchanged form in rats, suggesting that hepatic transporters play a major role in its clearance. Therefore, we investigated the transporters responsible for the hepatic uptake and biliary excretion of rosuvastatin. Uptake studies revealed that human organic anion transporting polypeptide (OATP) 1B1, OATP1B3, and OATP2B1 accept rosuvastatin as a substrate. Among the OATP family transporters, OATP1B1 contributes predominantly to the hepatic uptake of rosuvastatin, as estimated with the previously published relative activity factor method, and OATP1B3 is also partly involved. Significant vectorial basal-to-apical transport was observed in OATP1B1/multidrug resistance-associated protein 2 (MRP2), OATP1B1/multidrug resistance protein 1 (MDR1), and OATP1B1/breast cancer resistance protein (BCRP) double transfectants compared with that in an OATP1B1 single transfectant or in vector-transfected control cells. The ATP-dependent uptake of rosuvastatin by human BCRP-expressing membrane vesicles was significantly higher than the uptake by green fluorescent protein-expressing control vesicles, suggesting that MRP2, MDR1, and BCRP can transport rosuvastatin. Under in vivo conditions, the biliary excretion clearances based on the intrahepatic concentration of the parent rosuvastatin in Eisai hyper-bilirubinemic rats and Bcrp1 knockout mice were reduced to 53% and 12% of those in the control Sprague- Dawley rats and FVB mice, respectively, indicating that rat Mrp2 and mouse Bcrp1 are both partly involved in the biliary excretion of rosuvastatin. These results suggest that multiple transporters are involved in the hepatic uptake and efflux of rosuvastatin.