Kitamura Satoshi, Maeda Kazuya, Wang Yi, Sugiyama Yuichi
Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Drug Metab Dispos. 2008 Oct;36(10):2014-23. doi: 10.1124/dmd.108.021410. Epub 2008 Jul 10.
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 hyperbilirubinemic 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.
瑞舒伐他汀是一种HMG-CoA还原酶抑制剂，也是市售他汀类药物中亲水性最强的药物之一。在大鼠体内，它能有效地蓄积于肝脏，并以原形排泄到胆汁中，这表明肝脏转运体在其清除过程中起主要作用。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体。摄取研究表明，人类有机阴离子转运多肽（OATP）1B1、OATP1B3和OATP2B1可将瑞舒伐他汀作为底物。在OATP家族转运体中，根据先前发表的相对活性因子法估计，OATP1B1对瑞舒伐他汀的肝脏摄取起主要作用，OATP1B3也部分参与其中。与OATP1B1单转染细胞或载体转染对照细胞相比，在OATP1B1/多药耐药相关蛋白2（MRP2）、OATP1B1/多药耐药蛋白1（MDR1）和OATP1B1/乳腺癌耐药蛋白（BCRP）双转染细胞中观察到了显著的从基底到顶端的向量转运。表达人BCRP的膜囊泡对瑞舒伐他汀的ATP依赖性摄取显著高于表达绿色荧光蛋白的对照囊泡，这表明MRP2、MDR1和BCRP均可转运瑞舒伐他汀。在体内条件下，基于依斯艾力高胆红素血症大鼠和Bcrp1基因敲除小鼠体内母体瑞舒伐他汀肝内浓度的胆汁排泄清除率分别降至对照Sprague-Dawley大鼠和FVB小鼠的53%和12%，这表明大鼠Mrp2和小鼠Bcrp1均部分参与瑞舒伐他汀的胆汁排泄。这些结果表明，多种转运体参与了瑞舒伐他汀的肝脏摄取和外排。
