Long-Lasting Inhibition of the Transporter-Mediated Hepatic Uptake of Sulfobromophthalein by Cyclosporin A in Rats
Long-Lasting Inhibition of the Transporter-Mediated Hepatic Uptake of Sulfobromophthalein by Cyclosporin A in Rats
复制标题
DOI：
10.1124/dmd.108.025544
复制
发表时间：
2009-06-01
影响因子：
3.9
通讯作者：
Horie, Toshiharu
中科院分区：
文献类型：
--
作者：
Shitara, Yoshihisa;Nagamatsu, Yoshiko;Horie, Toshiharu
环孢菌素A(CsA)是有机阴离子转运多肽(OATP/Oatp)家族转运蛋白的抑制剂，在临床上可引起大量转运蛋白介导的药物相互作用。在本研究中，我们研究了CsA对大鼠肝脏对磺基溴邻苯二甲酸(BSP)摄取的抑制作用，重点是一种长期的抑制作用。皮下注射CsA后21h，BSP的肝清除率降低。肝脏摄取指数研究显示，CsA治疗至少3天后，大鼠肝脏对BSP的摄取减少。用从对照组和CsA处理的大鼠分离的肝细胞进行摄取研究的比较表明，CsA处理的大鼠的肝脏摄取减少。在原代培养的肝细胞中，用CsA预先孵育后，即使在从孵育缓冲液中去除CsA后，[H-3]BSP的摄取也减少了，尽管没有观察到预先孵育的时间依赖性。然而，参与肝脏摄取BSP的Oatp1a1和Oatp1b2的表达以及Oatp1a1的驱动力-肝内谷胱甘肽的量在CsA处理后没有改变。因此，我们可以得出结论，CSA对转运蛋白功能的调节是可持续的。它可以在体内引起强大的药物-药物相互作用。转运蛋白的调节不是由于转运蛋白的表达减少或驱动力减弱所致。它可能受到CsA在肝脏或其代谢产物中积聚的影响。CsA对转运体介导的BSP摄取的抑制作用不能用简单的竞争机制来解释，应该考虑一种新的机制。
Cyclosporin A (CsA) is a well known inhibitor of the organic anion-transporting polypeptide (OATP/Oatp) family transporters, causing a large number of transporter-mediated drug-drug interactions in clinical situations. In the present study, we examined the inhibitory effect of CsA on the hepatic uptake of sulfobromophthalein (BSP) in rats, focusing on a long-lasting inhibition. Twenty-one hours after the subcutaneous administration of CsA, the hepatic clearance of BSP was decreased. The liver uptake index study revealed that hepatic uptake of BSP was reduced in CsA-treated rats for at least 3 days. Comparison of uptake studies using isolated hepatocytes prepared from control and CsA-treated rats showed that hepatic uptake in CsA-treated rats was decreased. In primary cultured hepatocytes, after preincubation with CsA, the uptake of [H-3] BSP was reduced even after removal of CsA from the incubation buffer although a preincubation time dependence was not observed. However, the expression of Oatp1a1 and Oatp1b2, which are involved in the hepatic uptake of BSP, and the amount of intrahepatic glutathione, a driving force of Oatp1a1, did not change in CsA-treated rats. Thus, we can conclude that CsA modulates the transporter function sustainably. It can cause a potent in vivo drug-drug interaction. The modulation of transporters is not caused by reduced expression or driving force of transporters. It may be affected by CsA accumulated in the liver or its metabolites. The inhibitory effect of CsA on the transporter-mediated uptake of BSP cannot be explained by a simple competitive mechanism and a novel mechanism should be considered.