Drug-drug interaction between pitavastatin and various drugs via OATP1B1
Drug-drug interaction between pitavastatin and various drugs via OATP1B1
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DOI：
10.1124/dmd.106.009290
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发表时间：
2006-07-01
影响因子：
3.9
通讯作者：
Sugiyama, Yuichi
中科院分区：
文献类型：
--
作者：
Hirano, Masaru;Maeda, Kazuya;Sugiyama, Yuichi
匹伐他汀是一种新型的高效HMG辅酶A还原酶抑制剂，已被证明主要通过有机阴离子转运多肽（OATP）1B 1被人肝细胞摄取。由于OATP 2B 1也位于人肝脏的基底外侧膜中，因此我们采用两种方法进一步证实OATP 2B 1对匹伐他汀的肝脏摄取的微小贡献。Western印迹分析显示，人肝细胞中OATP 2B 1的条带密度与我们的表达系统中的条带密度之比至少比OATP 1B 1和OATP 1B 3低6倍。雌酮-3-硫酸酯（OATP 1B 1/OATP 2B 1抑制剂）和雌二醇-17 β-D-葡糖苷酸（OATP 1B 1/OATP 1B 3抑制剂）均可抑制人肝细胞中匹伐他汀的摄取。这些结果进一步支持OATP 1B 1是匹伐他汀肝脏摄取的主要转运蛋白的观点。然后，为了探索OATP 1B 1介导的药物相互作用的可能性，我们检查了各种药物对OATP 1B 1表达细胞中匹伐他汀摄取的抑制作用，并评估了体外抑制是否具有临床意义。正如我们以前报道的，我们使用的方法来估计在肝脏入口处的抑制剂的最大未结合浓度（I-u，I-in，I-max）。根据OATP 1B 1的Iu、in、max和抑制常数（K-i）判断，几种药物（尤其是环孢菌素A、利福平、利福霉素SV、克拉霉素和茚地那韦）可能与OATP 1B 1介导的匹伐他汀摄取相互作用。体外实验支持临床观察到的匹伐他汀与环孢素A之间的药物相互作用。提示在匹伐他汀的临床应用中应注意某些药物的联合应用。然后，为了探索OATP 1B 1介导的药物相互作用的可能性，我们检查了各种药物对OATP 1B 1表达细胞中匹伐他汀摄取的抑制作用，并评估了体外抑制是否具有临床意义。正如我们以前报道的，我们使用的方法来估计在肝脏入口处的抑制剂的最大未结合浓度（I-u，I-in，I-max）。根据OATP 1B 1的Iu、in、max和抑制常数（K-i）判断，几种药物（尤其是环孢菌素A、利福平、利福霉素SV、克拉霉素和茚地那韦）可能与OATP 1B 1介导的匹伐他汀摄取相互作用。体外实验支持临床观察到的匹伐他汀与环孢素A之间的药物相互作用。提示在匹伐他汀的临床应用中应注意某些药物的联合应用。
It has already been demonstrated that pitavastatin, a novel potent HMG-coenzyme A reductase inhibitor, is taken up into human hepatocytes mainly by organic anion transporting polypeptide (OATP) 1B1. Because OATP2B1 is also localized in the basolateral membrane of human liver, we took two approaches to further confirm the minor contribution of OATP2B1 to the hepatic uptake of pitavastatin. Western blot analysis revealed that the ratio of the band density of OATP2B1 in human hepatocytes to that in our expression system is at least 6-fold lower compared with OATP1B1 and OATP1B3. The uptake of pitavastatin in human hepatocytes could be inhibited by both estrone-3-sulfate (OATP1B1/OATP2B1 inhibitor) and estradiol-17 beta-D-glucuronide (OATP1B1/OATP1B3 inhibitor). These results further supported the idea that OATP1B1 is a predominant transporter for the hepatic uptake of pitavastatin. Then, to explore the possibility of OATP1B1-mediated drug-drug interaction, we checked the inhibitory effects of various drugs on the pitavastatin uptake in OATP1B1-expressing cells and evaluated whether the in vitro inhibition was clinically significant or not. As we previously reported, we used the methodology for estimating the maximum unbound concentration of inhibitors at the inlet to the liver (I-u,I-in,I-max). Judging from Iu, in, max and inhibition constant (K-i) for OATP1B1, several drugs (especially cyclosporin A, rifampicin, rifamycin SV, clarithromycin, and indinavir) have potentials for interacting with OATP1B1-mediated uptake of pitavastatin. The in vitro experiments could support the clinically observed drug-drug interaction between pitavastatin and cyclosporin A. These results suggest that we should pay attention to the concomitant use of some drugs with pitavastatin. Then, to explore the possibility of OATP1B1-mediated drug-drug interaction, we checked the inhibitory effects of various drugs on the pitavastatin uptake in OATP1B1-expressing cells and evaluated whether the in vitro inhibition was clinically significant or not. As we previously reported, we used the methodology for estimating the maximum unbound concentration of inhibitors at the inlet to the liver (I-u,I-in,I-max). Judging from Iu, in, max and inhibition constant (K-i) for OATP1B1, several drugs (especially cyclosporin A, rifampicin, rifamycin SV, clarithromycin, and indinavir) have potentials for interacting with OATP1B1-mediated uptake of pitavastatin. The in vitro experiments could support the clinically observed drug-drug interaction between pitavastatin and cyclosporin A. These results suggest that we should pay attention to the concomitant use of some drugs with pitavastatin.