| Project/Area Number |
11470495
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| Research Category |
Grant-in-Aid for Scientific Research (B).
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
医薬分子機能学
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
INUI Ken-ichi Kyoto University, Graduate School of Medicine, Professor, 医学研究科, 教授 (70034030)
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| Co-Investigator(Kenkyū-buntansha) |
MASUDA Satohiro Kyoto University, Graduate School of Medicine, Research Associate, 医学研究科, 助手 (90303825)
KATSURA Toshiya Kyoto University, Graduate School of Medicine, Research Associate, 医学研究科, 助手 (10283615)
SAITO Hideyuki Kyoto University, Graduate School of Medicine, Associate Professor, 医学研究科, 助教授 (40225727)
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| Project Period (FY) |
1999 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥14,700,000 (Direct Cost: ¥14,700,000)
Fiscal Year 2000: ¥5,500,000 (Direct Cost: ¥5,500,000)
Fiscal Year 1999: ¥9,200,000 (Direct Cost: ¥9,200,000)
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| Keywords | Organic cation transporter / Organic anion transporter / Kidney / Excretion / Tubular secretion / Drug transport / Drug interaction / ペプチドトランスポータ / CaCo^2細胞 / 性差 / H^+ / 3級アミン交換輸送系 / テトラエチルアンモニウム / P-糖タンパク質 |
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| Research Abstract |
We have studied the structure, function and tubular localization of organic ion transporters expressed in the kidney to systematically elucidate the mechanisms of renal excretion process of ionic drugs.
1. Organic cation transporter family : We demonstrated that OCT1 and OCT2 organic cation transporters recognized a variety of cationic drugs with similar substrate affinity. Immunocytochemical studies revealed that OCT1 and OCT2 were localized at the basolateral membrane of different tubular segments in the kidney. In addition, we found that the expression of OCT2, but not OCT1 and OCT3, was higher in the male kidney than the female kidney, and that the gender difference in OCT2 expression was regulated by sex hormones.
2. Organic anion transporter family : We have characterized the substrate specificity of organic anion transporters, OAT1 and OAT-K1, using various heterologous expression systems. OAT1 recognized relatively hydrophilic organic anions, while OAT-K1 transports hydrophobic organic anions. We demonstrated that OAT1-mediated transport of methotrexate was competitively inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin and salicylate, suggesting that OAT1 is the major site of the transporter-mediated interaction between methotrexate and NSAIDs. In addition, we succeeded in cloning of a new organic anion transporter, OAT-K2. Functional analysis indicated that OAT-K2 also recognized a variety of hydrophobic organic anions like OAT-K1.
These observations will help us to evaluate and predict the renal drug excretion. In addition, estimation of substrate affinity for each transporter could be useful to predict transporter-mediated drug interactions.
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