Anavex Life Sciences Corp (AVXL)

[Investor2014]

My reading of below is that although Donepezil and its metabolites stay in the body quite long, the drug undergoes significant hepatic (in the liver) metabolism. So my reading, hopefully not wrong, is not much bang for the buck compared to A2-73 who's metabolite penetrates the BBB and is also a potent and therapeutic compound.

Discussion
The results presented herein indicate that the primary route for the elimination of donepezil and its metabolites in human subjects is renal rather than biliary. This contrasts with findings from animal studies showing biliary excretion to be the primary route of elimination (unpublished observations).

In total, 72% of the administered dose was recovered, with approximately 57% recovered in the urine and 15% in the faeces. These findings are in agreement with previous studies, which showed that approximately four times more radioactivity was found in the urine than in the faeces [1, 2].

Although unchanged 14C-donepezil was present in both urine and plasma throughout the 240-h collection period, the results presented here demonstrate that donepezil undergoes significant hepatic metabolism. Three metabolic pathways are proposed on the basis of the results presented: (i) O-dealkylation followed by hydroxylation to metabolites M1 and M2, with partial subsequent glucuronidation to metabolites M11 and M12; (ii) hydrolysis to metabolite M4; and (iii) N-oxidation to metabolite M6 (Figure 2). Additional metabolic pathways may be operative, as represented by the number of unknown compounds observed. However, as each unknown metabolite represented an average of < 2% of the dose, these pathways are considered minor contributors to the metabolic process.

Metabolism and elimination of 14C-donepezil in healthy volunteers: a single-dose study