Organic Anion Transporting Polypeptides 1B1 and 1B3 Play an Important Role in Uremic Toxin Handling and Drug-Uremic Toxin Interactions in the Liver
Organic Anion Transporting Polypeptides 1B1 and 1B3 Play an Important Role in Uremic Toxin Handling and Drug-Uremic Toxin Interactions in the Liver
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DOI：
10.18433/j3m89q
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发表时间：
2014-01-01
影响因子：
2.7
通讯作者：
Mano, Nariyasu
中科院分区：
文献类型：
--
作者：
Sato, Toshihiro;Yamaguchi, Hiroaki;Mano, Nariyasu
目的.有机阴离子转运多肽（OATP）1B 1和OATP 1B 3有助于许多药物的肝脏摄取。因此，慢性肾脏疾病（CKD）患者的OATP 1B 1和OATP 1B 3活性降低可能对药物的肝脏清除率产生重大影响。尚未充分研究药物-尿毒症毒素相互作用对OATP 1B 1和OATP 1B 3的影响。在本研究中，我们检查了尿毒症毒素对OATP 1B 1和OATP 1B 3转运活性的抑制作用，以评价慢性肾脏疾病患者中药物与尿毒症毒素之间的相互作用。方法.通过表达OATP 1B 1和OATP 1B 3的HEK 293细胞进行[H-3]雌酮-3-硫酸盐、[H-3]牛磺胆酸盐摄取和[H-3]甲氨蝶呤，以评价尿毒症毒素的抑制作用。为了阐明与OATP 1B 1和/或OATP 1B 3相互作用的尿毒症毒素是否为这些转运蛋白的底物，我们进行了摄取研究。结果4种尿毒症毒素（犬尿烯酸、吲哚-3-乙酸、硫酸吲哚酚和对甲酚）以浓度依赖性方式抑制OATP 1B 1和OATP 1B 3介导的转运，OATP 1B 1的IC 50值分别为180、770、2700和4600 μ M，OATP 1B 3的IC 50值分别为180、1100、1300和1700 μ M。[H-3]四种尿毒症毒素也以剂量依赖性方式抑制OATP对甲氨蝶呤的摄取。摄取研究表明，犬尿烯酸是OATP 1B 1和OATP 1B 3的底物。此外，OATP 1B 3参与硫酸吲哚酚的转运。OATP 1B 1和OATP 1B 3对吲哚-3-乙酸和对甲酚的转运不显着。结论.我们发现一些尿毒症毒素以浓度依赖性方式抑制OATP介导的摄取，并阐明了OATP对肝脏中尿毒症毒素处理的贡献。因此，我们提供了基本信息，以估计尿毒症毒素对CKD患者OATP的抑制作用。这些数据表明，在CKD患者中，应仔细调整通过肾脏和非肾脏途径排泄的药物剂量。
PURPOSE. Organic anion-transporting polypeptide (OATP) 1B1 and OATP1B3 contribute to hepatic uptake of numerous drugs. Thus, reduced OATP1B1 and OATP1B3 activity in chronic kidney disease (CKD) may have a major impact on the hepatic clearance of drugs. The effect of drug-uremic toxin interactions on OATP1B1 and OATP1B3 has not been well studied. In the present study, we examine the inhibitory effects of uremic toxins on OATP1B1 and OATP1B3 transport activity to evaluate the interactions between drugs and uremic toxins in patients with chronic kidney disease. METHODS. [H-3]Estron-3-sulfate, [H-3]taurocholate uptake and [H-3]methotrexate by OATP1B1 and OATP1B3 expressing HEK293 cells were performed to evaluate the inhibitory effect of uremic toxins. To clarify whether the uremic toxins that interact with OATP1B1 and/or OATP1B3 were substrates for these transporters, we performed uptake studies. RESULTS. Four uremic toxins, kynurenic acid, indole-3-acetic acid, indoxyl sulfate, and p-cresol, inhibited OATP1B1- and OATP1B3-mediated transport in a concentration-dependent manner, with IC50 values of 180, 770, 2700, and 4600 mu M, respectively, for OATP1B1 and 180, 1100, 1300, and 1700 mu M, respectively, for OATP1B3. [H-3]Methotrexate uptake by OATPs was also inhibited by the four uremic toxins in a dose-dependent manner. Uptake studies revealed that kynurenic acid is a substrate for both the OATP1B1 and OATP1B3. Moreover, OATP1B3 was involved in the transport of indoxyl sulfate. Indole-3-acetic acid and p-cresol were not significantly transported by OATP1B1 and OATP1B3. CONCLUSIONS. We showed that some uremic toxins inhibit OATP-mediated uptake in a concentration-dependent manner, and clarified OATPs contribution to uremic toxin handling in the liver. Thus, we provided basic information to estimate the inhibitory effects of uremic toxins on OATPs in CKD patients. These data suggest that the dose of drugs excreted via renal and non-renal pathways should be carefully adjusted in CKD patients.