title: Local Drug-Drug Interaction of Donepezil with Cilostazol at Breast Cancer Resistance Protein (ABCG2) Increases Drug Accumulation in Heart.
abstract: 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).
authors.affiliation: 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.
authors.forename: Ryota
authors.initials: R
authors.lastname: Takeuchi
authors.affiliation: 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.
authors.forename: Kohki
authors.initials: K
authors.lastname: Shinozaki
authors.affiliation: 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.
authors.forename: Takeo
authors.initials: T
authors.lastname: Nakanishi
authors.affiliation: 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 tamai@p.kanazawa-u.ac.jp.
authors.forename: Ikumi
authors.initials: I
authors.lastname: Tamai
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D000166:Acridines / Q000494:pharmacology; D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D066126:Cardiotoxicity; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity; D000077407:Cilostazol; D004285:Dogs; D000077265:Donepezil; D004347:Drug Interactions; D005260:Female; D066298:In Vitro Techniques; D007189:Indans / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism*; D010880:Piperidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D017208:Rats, Wistar; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology* / Q000633:toxicity; D014018:Tissue Distribution; D014162:Transfection
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C489249:Abcg2 protein, rat; D000166:Acridines; D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D044005:Tetrahydroisoquinolines; D013777:Tetrazoles; D000077265:Donepezil; C083501:Elacridar; D000077407:Cilostazol