Donepezil(E 2020) is a specific and potent AChE inhibitor for bAChE and hAChE with IC50 of 8.12 nM and 11.6 nM, respectively.
Donepezil has reversible and noncompetitive inhibition effects on AChE. It has 500-1000-fold more selective for AChE over butyrylcholinesterase (BuChE). Short- and long-exposure of SH-SY5Y human neuroblastoma cells to donepezil induces a concentration-dependent inhibition of cell proliferation unrelated to muscarinic or nicotinic receptor blockade or apoptosis. Donepezil reduces the number of cells in the S-G2/M phases of the cell cycle, increases the G0/G1 population, and reduces the expression of two cyclins of the G1/S and G2/M transitions, cyclin E and cyclin B, in parallel with an increase in the expression of the cell cycle inhibitor p21.
Donepezil is metabolized in the liver via the cytochrome P450 system (CYP1A2-, CYP2D6-, CYP3A4-related enzymes). In animals, donepezil is found unchanged in brain, and no metabolites are detected in the nervous tissue. In plasma, urine, and bile, most donepezil metabolites are O-glucuronides. After oral ingestion, peak plasma concentrations are achieved in 3-5 hours and its absortion is not affected by food. Donepezil has linear pharmacokinetics over a dose range of 1-10 mg/day. 96% of circulating donepezil is protein bound.
|Cell lines||retinal ganglion cells (RGCs)|
|Preparation method||RGC survival after exposure to each reagent (glutamate, donepezil, tacrine, galanthamine, and HA14-1) is measured by calcein-AM staining after 3 days in culture, Briefly, cells are incubated in 1 μM calcein-AM in PBS for 15 minutes at 37℃. After the medium is replaced with fresh PBS, cells are examined under a fluorescence microscope using a fluorescein filter. The total number of surviving RGCs defined as cells with a calcein-AM stained cell body and a process extending at least two cell diameters from the cell body is counted in each well. The number of surviving RGCs without any drug served as a control.|
|Concentrations||100 nM-10 μM|
|Incubation time||3 days|
|Animal models||Age-matched (10-12 weeks old, 21–24 g) male C57BL/6 wild-type and CGRP(−/−) mice|
|Formulation||added to the food powder|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO: 70 mg/mL|
Donepezil in Alzheimer's disease: From conventional trials to pharmacogenetics.
Cacabelos R. Neuropsychiatr Dis Treat. 2007 Jun;3(3):303-33. PMID: 19300564.
Protective effect of donepezil on retinal ganglion cells in vitro and in vivo.
Miki A, et al. Curr Eye Res. 2006 Jan;31(1):69-77. PMID: 16421021.
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