| Co-Investigator(Kenkyū-buntansha) |
TAKIKAWA Hajime Department of Medicine, Teikyo University School of Medicine, Professor, 医学部, 教授 (70197226)
KUSUHARA Hiroyuki Graduate School of Pharmaceutical Sciences, The University of Tokyo, Research Associate, 大学院・薬学系研究科, 助手 (00302612)
SUZUKI Hiroshi Graduate School of Pharmaceutical Sciences, The University of Tokyo, Associate Professor, 大学院・薬学系研究科, 助教授 (80206523)
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| Research Abstract |
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
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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
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