Donepezil hydrochloride (
donepezil:
E2020: (+/-)-2-[(1-benzylpiperidin-4-yl)methyl]-5,6-dimethoxy-
indan-1-one monohydrochloride)) is a centrally acting
acetylcholinesterase inhibitor developed for the treatment of
Alzheimer's disease. In the present study, its inhibitory effect on the activity of
cholinesterase ex vivo was evaluated in the brain, plasma, erythrocytes, heart, small intestine, liver and pectoral muscle of young adult as well as aged rats, in comparison with that of
tacrine (9-amino-1,2,3,4-tetrahydroacridine hydrochloride). In aged animals,
cholinesterase activity in heart, small intestine and pectoral muscle was lower, whereas that in plasma and liver was higher than in young rats. Both groups showed the highest levels in the brain.
Donepezil, at doses of 1.25, 2.5 and 5 mg/kg, p.o., inhibited brain, plasma, erythrocyte, liver and pectoral muscle
cholinesterase activity in young rats in a dose-dependent manner but had less effect on
cholinesterase activity in heart and small intestine. In aged animals, inhibition of
cholinesterase activity in the brain, erythrocytes and pectoral muscle by
donepezil was more potent than that in young animals.
Tacrine, at doses of 5, 10 and 20 mg/kg, p.o., dose-dependently inhibited
cholinesterase activity in all tissues of both young and aged animals, but most potently in heart, small intestine and liver. The inhibition of
cholinesterase activity by
tacrine in the brain, plasma, erythrocytes, heart and liver was more potent in aged rats than in tissues of young rats. Brain and plasma concentrations of unchanged
donepezil and
tacrine were measured in the same animals as used for the
cholinesterase inhibition study. Brain and plasma concentrations of
donepezil and
tacrine were higher in aged than in young animals. It is concluded that the inhibitory effects of
donepezil and
tacrine on
cholinesterase activity are greater in aged than in young rats, owing to differences in the tissue concentrations of these compounds between young and aged animals. It is also suggested that the effect of
donepezil on
cholinesterase activity is more tissue-selective than that of
tacrine.