Metabolism and elimination of 14C-donepezil in healthy volunteers: a single-dose study.
OBJECTIVE
The aim of this study was to investigate the metabolism and elimination of donepezil HCl in humans, following the administration of a single 5 mg (liquid) oral dose containing a mixture of unlabelled and 14C-labelled donepezil.


METHODS
This was an open-label, non-randomized study in healthy male volunteers (n = 8). Characterization of donepezil metabolism and elimination was performed by analysing blood, urine and faecal samples collected over a 10-day period following drug administration. Each collected sample was assayed for total radioactivity, and aliquots from specified time-points and/or pooled samples were assayed for the presence of donepezil metabolites by thin-layer chromatography (TLC). Donepezil concentrations in plasma were determined by HPLC.


RESULTS
Recovery of radioactivity in subject samples averaged 72% of the administered dose. Recovery of the administered dose in urine (57%) was significantly greater than that recovered in faeces (15%). Unchanged donepezil accounted for the largest component of the recovered dose in each matrix. Three metabolic pathways were identified: (i) O-dealkylation and hydroxylation to metabolites M1 and M2, with subsequent glucuronidation to metabolites M11 and M12; (ii) hydrolysis to metabolite M4; and (iii) N-oxidation to metabolite M6. In plasma, the parent compound accounted for about 25% of the dose recovered during each sampling period, as well as of the cumulative dose recovered. The recovered residue showed higher levels of the hydroxylated metabolites M1 and M2 than of their glucuronide conjugates M11 and M12, respectively. In urine, the parent compound accounted for 17%, on average, of the dose recovered from each pooled sample, as well as of the total recovered dose. The major metabolite was the hydrolysis product M4, followed by the glucuronidated conjugates M11 and M12. In faeces, the parent compound also predominated, although it accounted for only 1%, of the recovered dose. A large percentage of the radioactivity in faeces consisted of unidentified very polar metabolites, which were retained at the TLC origin. Of the extracted metabolites, the hydroxylation products M1 and M2 were the most abundant, followed by the hydrolysis product M4 and the N-oxidation product M6.


CONCLUSIONS
Donepezil is hepatically metabolized and the predominant route for the elimination of both parent drug and its metabolites is renal, as 79% of the recovered dose was found in the urine with the remaining 21% found in the faeces. Moreover, the parent compound, donepezil, is the predominant elimination product in urine. The major metabolites of donepezil include M1 and M2 (via O-dealkylation and hydroxylation), M11 and M12 (via glucuronidation of M1 and M2, respectively), M4 (via hydrolysis) and M6 (via N-oxidation).
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Eisai Inc., Glenpointe Centre West, Teaneck, NJ 07666-6741, USA.
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D000284:Administration, Oral; D000328:Adult; D002250:Carbon Radioisotopes; D002800:Cholinesterase Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000077265:Donepezil; D005243:Feces / Q000737:chemistry; D006801:Humans; D007189:Indans / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010880:Piperidines / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
D002250:Carbon Radioisotopes; D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D000077265:Donepezil