Abstract
Donepezil hydrochloride (Aricept) is a drug for the treatment of Alzheimer's disease. The absorption, distribution, metabolism, and excretion of donepezil were investigated in male Sprague-Dawley rats after a single oral administration. Orally administered 14C-labeled donepezil was absorbed rapidly. The plasma level of unchanged donepezil declined more rapidly than that of radioactivity, and the brain level of radioactivity declined almost in parallel with the plasma level of unchanged donepezil. The ratio of donepezil to total radioactivity in brain was 86.9 to 93.0%, indicating low permeability of the metabolites through the blood-brain barrier. No heterogeneous localization of radioactivity was recognized in the brain and the concentration in each part of the brain was 1.74 to 2.24 times the plasma concentration. Cumulative biliary, urinary, and fecal excretion of radioactivity in bile duct-cannulated rats was 72.9, 24.4, and 8.84%, respectively, of the administered radioactivity at 48 h after administration. These results indicate that the absorption of donepezil is almost complete, and that its metabolites are mainly excreted into feces through the bile and some of them are subject to enterohepatic circulation. The metabolism of donepezil was extensive in rats and involved O-demethylation, aromatic hydroxylation, N-dealkylation,N-oxidation, and glucuronide conjugation ofO-demethylate. The structures of the metabolites were determined by mass spectrometry and 1H-NMR analysis. In plasma, urine, and bile, O-glucuronides accounted for the majority of the radioactivity, and in brain, unchanged donepezil was mostly detected. No metabolites were found in brain. There was no notable accumulation of radioactivity in whole blood and tissues.
Footnotes
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Send reprint requests to: Kenji Matsui, Ph.D., Drug Dynamics Research Section, Drug Safety and Disposition Research Laboratories, Eisai Co., Ltd., 1–3 Tokodai 5-chome, Tsukuba-shi, Ibaraki 300-2635, Japan. E-mail: k2-matsui{at}eisai.co.jp
- Abbreviations used are::
- AUC
- area under the curve
- TLC
- thin-layer chromatography
- MS
- mass spectrometry
- NOE
- Nuclear Overhauser Effect
- BQL
- below quantification limit
- IS
- internal standard
- EI
- electron impact
- Received April 12, 1999.
- Accepted August 18, 1999.
- The American Society for Pharmacology and Experimental Therapeutics