| Project/Area Number |
26670075
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| Research Category |
Grant-in-Aid for Challenging Exploratory Research
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| Allocation Type | Multi-year Fund |
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| Research Field |
Medical pharmacy
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| Research Institution | Kanazawa University |
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Principal Investigator |
Tamai Ikumi 金沢大学, 薬学系, 教授 (20155237)
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| Co-Investigator(Kenkyū-buntansha) |
Nakanishi Takeo 金沢大学, 医薬保健研究域薬学系, 准教授 (30541742)
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| Co-Investigator(Renkei-kenkyūsha) |
Wakayama Tomohiko 熊本大学, 大学院生命科学研究部(医), 教授 (70305100)
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| Research Collaborator |
Takeuchi Ryota 金沢大学, 医薬保健学総合研究科
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| Project Period (FY) |
2014-04-01 – 2016-03-31
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| Project Status |
Completed (Fiscal Year 2015)
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| Budget Amount *help |
¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | 薬物間相互作用 / トランスポーター / BCRP / ドネペジル / シロスタゾール / Local DDI / Local-DDI / 薬物相互作用 / 心毒性 |
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| Outline of Final Research Achievements |
Clinical reports indicate that cardiotoxicity due to donepezil occurs after co-administration with cilostazol. We speculated that the concentration of donepezil in heart tissue might be increased by interaction with cilostazol at efflux transporter BCRP in heart. In this study, donepezil was found as a substrate of BCRP. Cilostazol inhibited BCRP with IC50 of 130 nM, which is less than clinically achievable unbound plasma cilostazol (about 200 nM). In in vivo rat study, we found that cilostazol significantly increased the donepezil concentrations in heart and brain, where BCRP functions as the blood-tissue barrier, whereas the plasma concentration of donepezil was unaffected. In addition, in vitro accumulation of donepezil in heart tissue slices of rats was significantly increased by cilostazol. Accordingly, donepezil-cilostazol interaction at BCRP may be clinically relevant in heart and brain without any apparent change in plasma concentration, resulting in side effect of donepezil.
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