Inhibitory effects of donepezil hydrochloride (E2020) on cholinesterase activity in brain and peripheral tissues of young and aged rats

Donepezil hydrochloride (donepezil: E2020: (+/-)-2-[(1-benzylpiperidin-4-yl )methyl]-5,6-dimethoxy-indan-1-one monohydrochloride)) is a centrally actin g acetylcholinesterase inhibitor developed for the treatment of Alzheimer's disease. In the present study, its inhibitory effect on the activity of ch olinesterase ex vivo was evaluated in the brain, plasma, erythrocytes, hear t, small intestine, liver and pectoral muscle of young adult as well as age d rats, in comparison with that of tacrine (9-amino-1,2,3,4-tetrahydroacrid ine hydrochloride). In aged animals, cholinesterase activity in heart, smal l 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 th e brain. Donepezil, at doses of 1.25, 2.5 and 5 mg/kg, p.o., inhibited brai n, plasma, erythrocyte, liver and pectoral muscle cholinesterase activity i n young rats in a dose-dependent manner but had less effect on cholinestera se activity in heart and small intestine. In aged animals, inhibition of ch olinesterase activity in the brain, erythrocytes and pectoral muscle by don epezil 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 i n all tissues of both young and aged animals, but most potently in heart, s mall intestine and liver. The inhibition of cholinesterase activity by tacr ine 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 con cluded that the inhibitory effects of donepezil and tacrine on cholinestera se activity are greater in aged than in young rats, owing to differences in the tissue concentrations of these compounds between young and aged animal s. It is also suggested that the effect of donepezil on cholinesterase acti vity is more tissue-selective than that of tacrine. (C) 1999 Elsevier Scien ce B.V. All rights resented.