Hirano Masaru, Maeda Kazuya, Matsushima Soichiro, Nozaki Yoshitane, Kusuhara Hiroyuki, 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.
Mol Pharmacol. 2005 Sep;68(3):800-7. doi: 10.1124/mol.105.014019. Epub 2005 Jun 13.
Pitavastatin, a novel potent 3-hydroxymethylglutaryl coenzyme A reductase inhibitor, is distributed selectively to the liver and excreted into bile in unchanged form in rats. We reported previously that the hepatic uptake is mainly mediated by organic anion transporting polypeptide (OATP) 1B1, whereas the biliary excretion mechanism remains to be clarified. In the present study, we investigated the role of breast cancer resistance protein (BCRP) in the biliary excretion of pitavastatin. The ATP-dependent uptake of pitavastatin by human and mouse BCRP-expressing membrane vesicles was significantly higher compared with that by control vesicles with Km values of 5.73 and 4.77 microM, respectively. The biliary excretion clearance of pitavastatin in Bcrp1-/- mice was decreased to one-tenth of that in control mice. The biliary excretion of pitavastatin was unchanged between control and Eisai hyperbilirubinemic rats, indicating a minor contribution of multidrug resistance-associated protein (Mrp) 2. This observation differs radically from that for a more hydrophilic statin, pravastatin, of which biliary excretion is largely mediated by Mrp2. These data suggest that the biliary clearance of pitavastatin can be largely accounted for by BCRP in mice. In the case of humans, transcellular transport of pitavastatin was determined in the Madin-Darby canine kidney II cells expressing OATP1B1 and human canalicular efflux transporters. A significant basal-to-apical transport of pitavastatin was observed in OATP1B1/MDR1 and OATP1B1/MRP2 double transfectants as well as OATP1B1/BCRP double transfectants, implying the involvement of multiple transporters in the biliary excretion of pitavastatin in humans. This is in contrast to a previous belief that the biliary excretion of statins is mediated mainly by MRP2.
匹伐他汀是一种新型强效3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂，在大鼠体内可选择性地分布于肝脏，并以原形经胆汁排泄。我们之前报道过，肝脏摄取主要由有机阴离子转运多肽（OATP）1B1介导，而胆汁排泄机制仍有待阐明。在本研究中，我们研究了乳腺癌耐药蛋白（BCRP）在匹伐他汀胆汁排泄中的作用。与对照囊泡相比，表达人源和鼠源BCRP的膜囊泡对匹伐他汀的ATP依赖性摄取显著更高，其Km值分别为5.73和4.77微摩尔。在Bcrp1-/-小鼠中，匹伐他汀的胆汁排泄清除率降至对照小鼠的十分之一。在对照大鼠和卫材高胆红素血症大鼠之间，匹伐他汀的胆汁排泄没有变化，表明多药耐药相关蛋白（Mrp）2的作用较小。这一观察结果与更亲水性的他汀类药物普伐他汀截然不同，普伐他汀的胆汁排泄主要由Mrp2介导。这些数据表明，在小鼠中，匹伐他汀的胆汁清除主要由BCRP负责。在人类中，在表达OATP1B1和人胆小管外排转运体的Madin-Darby犬肾II细胞中测定了匹伐他汀的跨细胞转运。在OATP1B1/MDR1和OATP1B1/MRP2双转染细胞以及OATP1B1/BCRP双转染细胞中均观察到匹伐他汀从基底侧到顶端的显著转运，这意味着多种转运体参与了人类中匹伐他汀的胆汁排泄。这与之前认为他汀类药物的胆汁排泄主要由MRP2介导的观点相反。
