Takeuchi Ryota, Shinozaki Kohki, Nakanishi Takeo, Tamai Ikumi
Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa (R.T., T.N., I.T.) and Hikuma Pharmacy, Hamamatsu (K.S.), Japan.
Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa (R.T., T.N., I.T.) and Hikuma Pharmacy, Hamamatsu (K.S.), Japan
Drug Metab Dispos. 2016 Jan;44(1):68-74. doi: 10.1124/dmd.115.066654. Epub 2015 Oct 14.
Clinical reports indicate that cardiotoxicity due to donepezil can occur after coadministration with cilostazol. We speculated that the concentration of donepezil in heart tissue might be increased as a result of interaction with cilostazol at efflux transporters such as P-glycoprotein (P-gp, ABCB1) and breast cancer resistance protein (BCRP, ABCG2), which are expressed in many tissues including the heart, and our study tested this hypothesis. First, donepezil was confirmed to be a substrate of both BCRP and P-glycoprotein in transporter-transfected cells in vitro. Cilostazol inhibited BCRP and P-glycoprotein with half-inhibitory concentrations of 130 nM and 12.7 μM, respectively. Considering the clinically achievable unbound plasma concentration of cilostazol (about 200 nM), it is plausible that BCRP-mediated transport of donepezil would be affected by cilostazol in vivo. Indeed, in an in vivo rat study, we found that coadministration of cilostazol significantly increased the concentrations of donepezil in the heart and brain, where BCRP functions as a part of 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 in the presence of cilostazol. These results indicate that donepezil-cilostazol interaction at BCRP may be clinically relevant in heart and brain tissues. In other words, the tissue distribution of drugs can be influenced by drug-drug interaction (DDI) at efflux transporters in certain tissues (local DDI) without any apparent change in plasma concentration (systemic DDI).
临床报告表明，多奈哌齐与西洛他唑合用时可能会发生心脏毒性。我们推测，由于多奈哌齐与西洛他唑在诸如P-糖蛋白（P-gp，ABCB1）和乳腺癌耐药蛋白（BCRP，ABCG2）等外排转运蛋白上相互作用，多奈哌齐在心脏组织中的浓度可能会升高，这些转运蛋白在包括心脏在内的许多组织中均有表达，我们的研究对这一假设进行了验证。首先，在体外转运蛋白转染细胞中证实多奈哌齐是BCRP和P-糖蛋白的底物。西洛他唑抑制BCRP和P-糖蛋白，其半数抑制浓度分别为130 nM和12.7 μM。考虑到西洛他唑临床可达到的未结合血浆浓度（约200 nM），BCRP介导的多奈哌齐转运在体内可能会受到西洛他唑的影响，这似乎是合理的。事实上，在一项体内大鼠研究中，我们发现西洛他唑与多奈哌齐合用时，显著增加了心脏和大脑中多奈哌齐的浓度，在这些部位BCRP作为血组织屏障的一部分发挥作用，而多奈哌齐的血浆浓度未受影响。此外，在西洛他唑存在的情况下，大鼠心脏组织切片中多奈哌齐的体外蓄积显著增加。这些结果表明，多奈哌齐与西洛他唑在BCRP上的相互作用在心脏和脑组织中可能具有临床相关性。换句话说，在某些组织（局部药物相互作用）中，药物在流出转运体上的药物-药物相互作用（DDI）可影响药物的组织分布，而血浆浓度（全身DDI）没有任何明显变化。
