title: Postmortem redistribution mechanism of donepezil in the rat.
abstract: Population aging is rapidly advancing in numerous parts of the world and, accordingly, the prevalence of Alzheimer's disease (AD) is rising. The safety of donepezil (DPZ), which is used for AD treatment, has been established in clinical trials. However, some studies have indicated that DPZ may be associated with severe cardiac side effects, and excessive doses may induce toxicity-related symptoms or death. Therefore, the measurement of blood DPZ levels is important for the postmortem investigation of related causes of death. However, postmortem drug concentrations in the blood may not always reflect those obtained antemortem because of the postmortem redistribution (PMR) of drugs. Therefore, the aim of this study was to investigate the potential PMR of DPZ using a rat model. The DPZ concentration was measured using a validated HPLC/Q-TOF-MS system in cardiac and peripheral blood, and in the brain, lungs, myocardium, liver, and thigh muscle at different postmortem intervals (0, 1, 3, 6, 12, and 24h). Overall, the DPZ tissue to peripheral blood ratio decreased throughout the postmortem period. Furthermore, the DPZ concentration increased in the peripheral and cardiac blood but decreased in both of the lungs, postmortem. Furthermore, the blood pH was significantly lowered. We used a perfusion approach to examine the rat lung and heart to further investigate the relationship between the pH and DPZ release from the lungs. The outflow concentrations when the inflow pH changed from 7.4 to 5.5 were approximately 2-fold higher than the inflow pH fixed 7.4. These findings suggest that the antemortem accumulated DPZ in the lungs is released into the pulmonary blood owing to postmortem acidification of blood, and subsequently flows into the cardiac blood, leading to the observed increase in concentration. Although we could not determine the underlying mechanism, we confirmed that PMR occurs similarly in the cardiac and peripheral blood.
authors.affiliation: Department of Legal Medicine, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba city, Chiba 260-8670, Japan. Electronic address: nagasawa.s@chiba-u.jp.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Nagasawa
authors.affiliation: Narcotics Control Department, Kanto-Shin'etsu Regional Bureau of Health and Welfare, Kudan-Minami 1-2-1, Chiyoda-ku, Tokyo 102-8309, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Katagiri
authors.affiliation: Department of Legal Medicine, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba city, Chiba 260-8670, Japan.
authors.forename: Akina
authors.initials: A
authors.lastname: Nara
authors.affiliation: Department of Legal Medicine, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba city, Chiba 260-8670, Japan; Department of Forensic Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Chiba
authors.affiliation: Department of Legal Medicine, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba city, Chiba 260-8670, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kubo
authors.affiliation: Department of Legal Medicine, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba city, Chiba 260-8670, Japan; Department of Forensic Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Suguru
authors.initials: S
authors.lastname: Torimitsu
authors.affiliation: Department of Legal Medicine, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba city, Chiba 260-8670, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yajima
authors.affiliation: Narcotics Control Department, Kanto-Shin'etsu Regional Bureau of Health and Welfare, Kudan-Minami 1-2-1, Chiyoda-ku, Tokyo 102-8309, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Akutsu
authors.affiliation: Department of Legal Medicine, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba city, Chiba 260-8670, Japan; Department of Forensic Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Hirotaro
authors.initials: H
authors.lastname: Iwase
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000473:pathology; D000818:Animals; D001344:Autopsy; D001774:Blood Chemical Analysis; D002800:Cholinesterase Inhibitors / Q000032:analysis / Q000097:blood / Q000378:metabolism* / Q000627:therapeutic use; D000077265:Donepezil; D006863:Hydrogen-Ion Concentration; D007189:Indans / Q000032:analysis / Q000097:blood / Q000378:metabolism* / Q000627:therapeutic use; D010880:Piperidines / Q000032:analysis / Q000097:blood / Q000378:metabolism* / Q000627:therapeutic use; D011180:Postmortem Changes; D051381:Rats; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D000077265:Donepezil
keywords: Alzheimer's disease; Donepezil; LC/TOF/MS; Perfusion; Postmortem redistribution