Development of the system for prediction of drug-drug interactions in hepatobiliary transport process

肝胆转运过程中药物相互作用预测系统的开发

基本信息

批准号：
13557219
负责人：
SUGIYAMA Yuichi
金额：
$ 8.45万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13557219/
关键词：
transporter drug-drug interaction OATP2 MRP2 hepatobiliary transport OCT cerivastatin biguanides OCT1 OCT2

项目摘要

1. We succeeded in the construction of human and rat double transfectants which express human organic anion transporting polypeptide(OATP) 2 and multidrug resistance asssociated protein 2 (MRP2), and rat Oatp4 and Mrp2, respectively. We confirmed that OATP2(Oatp4) and MRP2 expressed on the basal and apical side, which is consistent with the physiological polarized expression pattern in liver. In this system, OATP2(Oatp4)/MRP2 bisubstrates such as estradiol-17β-glucuronide and pravastatin can be transported from the basal to apical compartment efficiently, compared with other direction. Moreover, rat in vivo hepatic clearance was well correlated with transcellular clearance of rat double transfectant by multiplying a scaling factor, which suggested that this system may be able to utilize the prediction of in vivo hepatic clearance.2. To evaluate the side effects and drug-drug interactions in the clinical situations, which we hypothesized the involvement of transporters, we analyzed the … More mechanism of drug-drug interaction between cyclosporin A(CyA) and cerivastatin(CER) using OATP2 expression system and human cryopreserved hepatocytes. In result, CyA potently inhibited the OATP2-mediated CER uptake and its inhibition constant was almost comparable with that of human hepatocytes and clinical unbound concentration of CyA. On the other hand, CyA slightly inhibited CER metabolism by CYP enzymes. So we suggested that one of the interaction mechanism is inhibition of hepatic uptake process mediated by OATP2. To investigate the mechanism for the expression of severe side effects (lactic acidosis) of biguanides(antidiabetes drugs), we performed the transport assay using human organic cation transporter(OCT)1 and 2 expression system to check their transport mechanism in liver and kidney. Biguanides can be transported by OCT1 and OCT2, which suggested that OCT1 is involved in hepatic uptake, whereas OCT2 in renal uptake and that OCT1-mediated hepatic uptake may be one of the trigger for lactic acidosis. Less

1.我们成功构建了表达人有机阴离子转运多肽（OATP）2和多药耐药相关蛋白2（MRP2）的人和大鼠双转染子，并分别证实了OATP2（Oatp4）和Mrp2。 MRP2在基底侧和顶端侧表达，这与肝脏中的生理极化表达模式一致。与其他方向相比，OATP2(Oatp4)/MRP2 双底物如雌二醇-17β-葡萄糖醛酸和普伐他汀可以有效地从基底室转运至顶端室，而且，大鼠体内肝脏清除率与大鼠双转染子的跨细胞清除率良好相关。乘以比例因子，这表明该系统可能能够利用体内肝清除率的预测。2．在临床情况下，我们开发了转运蛋白的参与，我们使用 OATP2 表达系统和人冻存肝细胞分析了环孢菌素 A (CyA) 和西立伐他汀 (CER) 之间的药物相互作用机制。 CyA 抑制 OATP2 介导的 CER 摄取，其抑制常数几乎与人肝细胞和未结合的 CyA 临床浓度相当。 CYP酶抑制CER代谢，因此我们认为相互作用机制之一是抑制OATP2介导的肝脏摄取过程。为了研究双胍类药物（抗糖尿病药物）严重副作用（乳酸性酸中毒）的表达机制。利用人有机阳离子转运蛋白（OCT）1和2表达系统进行转运实验，检查双胍类药物在肝脏和肾脏中的转运机制，表明OCT1和OCT2可以转运双胍类药物。 OCT1参与肝脏摄取，而OCT2参与肾脏摄取，并且OCT1介导的肝脏摄取可能是乳酸性酸中毒的触发因素之一。