Absorption, distribution, metabolism, and excretion of donepezil (ARICEPT)after a single oral administration to rat

Donepezil hydrochloride (Aricept) is a drug for the treatment of Alzheimer' s disease. The absorption, distribution, metabolism, and excretion of donep ezil were investigated in male Sprague-Dawley rats after a single oral admi nistration. Orally administered C-14-labeled donepezil was absorbed rapidly . The plasma level of unchanged donepezil declined more rapidly than that o f radioactivity, and the brain level of radioactivity declined almost in pa rallel with the plasma level of unchanged donepezil. The ratio of donepezil to total radioactivity in brain was 86.9 to 93.0%, indicating low permeabi lity of the metabolites through the blood-brain barrier. No heterogeneous l ocalization of radioactivity was recognized in the brain and the concentrat ion in each part of the brain was 1.74 to 2.24 times the plasma concentrati on. Cumulative biliary, urinary, and fecal excretion of radioactivity in bi le duct-cannulated rats was 72.9, 24.4, and 8.84%, respectively, of the adm inistered radioactivity at 48 h after administration. These results indicat e that the absorption of donepezil is almost complete, and that its metabol ites are mainly excreted into feces through the bile and some of them are s ubject to enterohepatic circulation. The metabolism of donepezil was extens ive in rats and involved O-demethylation, aromatic hydroxylation, N-dealkyl ation, N-oxidation, and glucuronide conjugation of O-demethylate. The struc tures of the metabolites were determined by mass spectrometry and H-1-NMR a nalysis. In plasma, urine, and bile, O-glucuronides accounted for the major ity of the radioactivity, and in brain, unchanged donepezil was mostly dete cted. No metabolites were found in brain. There was no notable accumulation of radioactivity in whole blood and tissues.