Hirano Masaru, Maeda Kazuya, Hayashi Hisamitsu, 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.
J Pharmacol Exp Ther. 2005 Aug;314(2):876-82. doi: 10.1124/jpet.105.084830. Epub 2005 May 18.
Pravastatin is a well known 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor. Cumulative studies have shown that pravastatin is taken up into hepatocytes by the organic anion transporting polypeptide family transporters and excreted into the bile as an intact form by multidrug resistance-associated protein 2 (MRP2). It is generally accepted that the bile salt export pump (BSEP/ABCB11) mainly transports bile acids and plays an indispensable role in their biliary excretion. Interestingly, we found that BSEP could accept pravastatin as a substrate. Significant ATP-dependent uptake of pravastatin by human BSEP (hBSEP)- and rat BSEP (rBsep)-expressing membrane vesicles was observed, and the ratio of the uptake activity of pravastatin to that of taurocholic acid (TCA) by hBSEP was 3.3-fold higher than that by rBsep. The K(m) value of pravastatin for hBSEP was 124 muM. A mutual inhibition study between TCA and pravastatin revealed that they competitively interact with hBSEP. Several statins inhibited the hBSEP- and rBsep-mediated uptake of TCA; however, the specific uptake of other statins (cerivastatin, fluvastatin, and pitavastatin) by hBSEP and rBSEP was not detected. The inhibitory effects of hydrophilic statins (pravastatin and rosuvastatin) on the uptake of TCA by BSEP were relatively lower than those of lipophilic statins. These data suggest that BSEP may be partly involved in the biliary excretion of pravastatin in both rats and humans.
普伐他汀是一种知名的3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂。累积研究表明，普伐他汀通过有机阴离子转运多肽家族转运体被摄取到肝细胞中，并通过多药耐药相关蛋白2（MRP2）以完整形式排泄到胆汁中。人们普遍认为胆盐输出泵（BSEP/ABCB11）主要转运胆汁酸，并在其胆汁排泄中发挥不可或缺的作用。有趣的是，我们发现BSEP可以接受普伐他汀作为底物。观察到表达人BSEP（hBSEP）和大鼠BSEP（rBsep）的膜囊泡对普伐他汀有显著的ATP依赖性摄取，hBSEP对普伐他汀的摄取活性与牛磺胆酸（TCA）的摄取活性之比比rBsep高3.3倍。普伐他汀对hBSEP的K（m）值为124μM。TCA和普伐他汀之间的相互抑制研究表明它们与hBSEP竞争性相互作用。几种他汀类药物抑制hBSEP和rBsep介导的TCA摄取；然而，未检测到其他他汀类药物（西立伐他汀、氟伐他汀和匹伐他汀）被hBSEP和rBSEP特异性摄取。亲水性他汀类药物（普伐他汀和瑞舒伐他汀）对BSEP摄取TCA的抑制作用相对低于亲脂性他汀类药物。这些数据表明，BSEP可能在大鼠和人类中都部分参与了普伐他汀的胆汁排泄。
