title: Donepezil distribution in postmortem cases and potential for redistribution.
abstract: Donepezil (DPZ) is an acetylcholine-esterase inhibitor currently used as the frontline drug to treat Alzheimer's disease. The aim of this study was to investigate the possibility of postmortem redistribution (PMR) of DPZ, which could complicate the determination of cause of death in medico-legal cases. Additionally, metabolic enzyme DNA polymorphism, drug-drug interaction and the presence of lesions in metabolic and egestion organs were examined to eliminate the possibility of a high antemortem DPZ concentration. Subsequently, the average DPZ concentration of four sites of peripheral blood (right and left femoral artery and vein) was compared with central blood and liver DPZ concentrations in seven postmortem cases. DPZ concentrations ranged from 0.02 to 0.45μg/mL in the peripheral blood, 0.09-0.4μg/mL in central blood, and from 1.2 to 6.7μg/kg in the liver. In most specimens, the concentrations were higher than the therapeutic range (approximately 0.030-0.075μg/mL). DPZ central blood to peripheral blood (C/P) ratios averaged 1.73±1.02 (±standard deviation) while liver to peripheral blood (L/P) ratios were higher and averaged 17.5±7.25. It is documented that a C/P ratio of less than (or about) 1.0 and an L/P ratio less than 5 are not indicative of PMR, whereas a C/P ratio exceeding 2 and L/P ratio exceeding 20 highlight a propensity for significant PMR. Our data suggest that DPZ exhibits a moderate degree of PMR. Additionally, a lowered pH was found in all blood specimens (<6-6.75 in the peripheral blood and <6-6.66 in the central blood). This postmortem reduction in blood pH may increase the ionic forms of DPZ, resulting in a high blood DPZ concentration.
authors.affiliation: Department of Legal Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. Electronic address: nagasawa.s@chiba-u.jp.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Nagasawa
authors.affiliation: Department of Legal Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, 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, 1-8-1 Inohana, Chuo-ku, 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, 1-8-1 Inohana, Chuo-ku, 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, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yajima
authors.affiliation: Department of Legal Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, 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: D000369:Aged, 80 and over; D001774:Blood Chemical Analysis; D002800:Cholinesterase Inhibitors / Q000032:analysis / Q000493:pharmacokinetics*; D002853:Chromatography, Liquid; D000077265:Donepezil; D005260:Female; D053593:Forensic Toxicology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007189:Indans / Q000032:analysis / Q000493:pharmacokinetics*; D008099:Liver / Q000737:chemistry; D013058:Mass Spectrometry; D010880:Piperidines / Q000032:analysis / Q000493:pharmacokinetics*; D011180:Postmortem Changes; D014018:Tissue Distribution
chemical_list: D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D000077265:Donepezil
keywords: Central blood; Donepezil; LC/MS/MS; Liver; Peripheral blood; Postmortem redistribution