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2015 Fiscal Year Final Research Report

Local drug-drug interaction of donepezil with cilostazol at BCRP transporter

Research Project

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Project/Area Number 26670075
Research Category

Grant-in-Aid for Challenging Exploratory Research

Allocation TypeMulti-year Fund
Research Field Medical pharmacy
Research InstitutionKanazawa University

Principal Investigator

Tamai Ikumi  金沢大学, 薬学系, 教授 (20155237)

Co-Investigator(Kenkyū-buntansha) Nakanishi Takeo  金沢大学, 医薬保健研究域薬学系, 准教授 (30541742)
Co-Investigator(Renkei-kenkyūsha) Wakayama Tomohiko  熊本大学, 大学院生命科学研究部(医), 教授 (70305100)
Research Collaborator Takeuchi Ryota  金沢大学, 医薬保健学総合研究科
Project Period (FY) 2014-04-01 – 2016-03-31
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
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.

Free Research Field

薬物動態学

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Published: 2017-05-10  

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