Local Drug-Drug Interaction of Donepezil with Cilostazol at Breast Cancer Resistance Protein (ABCG2) Increases Drug Accumulation in Heart.

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).

[Risk management of QT-prolonging drugs by community pharmacists using a mobile electrocardiograph].

Prolongation of the QT interval is associated with a high risk of serious arrhythmia, i.e., torsades de pointes (TdP). However, in many cases, the QT-prolonging drug(s) is prescribed without performing a thorough check-up of the patient's condition, especially an electrocardiogram. In addition to patient interview, we used an electrocardiogram obtained with a mobile electrocardiograph (RMH-ECG) in a community pharmacy in order to improve the risk management for QT-prolonging drugs. A comparison of the results obtained using RMH-ECG (modified I) and 12-lead ECG (I) revealed that both corrected QT (QTc) values were almost identical, and the correlation coefficient was 0.96. In one month, 5 of 948 patients who visited our pharmacy and continuously took QT-prolonging drugs had additional risk factors for TdP (advanced age, female, and drug-drug interaction). We monitored the QT interval of one of these patients. She had received erythromycin for 19 months along with other drugs metabolized by a P450 (CYP3A4); benidipine and prednisolone (for over 2 years), and tacrolimus (for 13 weeks). Three RMH-ECG tests at every 2 weeks revealed that QTcs were normal (0.43-0.45 s); therefore, we dispensed drugs without any change in the prescription. Approximately 1 in 1200 individuals has a prolonged QT interval without any subjective symptoms, and the time window of drug-induced TdP is considered to be from several hours to months after taking these drugs. Therefore, we think that an ECG test should be performed in community pharmacies before dispensing QT-prolonging drugs and that the QT interval should be monitored.

[Shortening of donepezil-induced QTc prolongation with a change in the interacting drug, after electrocardiograph monitoring by community pharmacists: a case report].

UNLABELLED: We used a mobile electrocardiograph to manage the adverse effects and interactions of drugs, especially QT-prolonging drugs, in a community pharmacy setting. We report the case of a patient in whom the risk of drug-induced torsades de pointes (TdP) was lowered, after monitoring by community pharmacists. CASE: An 80-year-old woman was under donepezil (5 mg/d) therapy for Alzheimer's disease and also taking other drugs that interact with donepezil, namely, benidipine (8 mg/d) and atorvastatin (10 mg/d). The patient was visited almost every month, and an electrocardiogram was usually obtained. QTc prolongation (avg. 470±9 ms) was observed in the first to third tests. Her doctor was informed about these results and the risk factors (advanced age, gender, and drugs interactions (benidipine and atorvastatin)) associated with TdP and asked to respond promptly since several cases of donepezil-induced TdP have been reported. As a result, benidipine was replaced with amlodipine, while the remaining drugs were continued. After the change, a significant decrease in QTc values were observed in the fourth to seventh tests (avg. 441±9 ms, p=0.010), thereby indicating a decrease in TdP risk. The Drug Interaction Probability Scale (object drug, donepezil; precipitant drug, benidipine) score was +6 (probable). Thus, QTc shortening was a result of differences in donepezil-benidipine and donepezil-amlodipine interactions.