Inhibitory effect of orally administered donepezil hydrochloride (E2020), a novel treatment for Alzheimer's disease, on cholinesterase activity in rats

Donepezil hydrochloride ((±)-2-[(1-benzylpiperidin-4-yl)methyl]-5,6-dimethoxy-indan-1-one monohydrochloride: E2020: donepezil) is a potent and selective acetylcholinesterase inhibitor developed for the treatment of Alzheimer's disease. The present experiments were designed to compare the inhibitory effects of orally administered donepezil and other cholinesterase inhibitors, tacrine (9-amino-1,2,3,4-tetrahydroacridine hydrochloride), ( S)- N-ethyl-3-[(1-dimethyl-amino)ethyl]- N-methyl-phenylcarbamate hydrogentartrate (ENA-713, rivastigmine) and 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1 H-1-benzazepin-8-yl)-1-propanone fumarate (TAK-147), on the cholinesterase activity in the brain and plasma of rats. Moreover, in order to validate the cholinesterase inhibition data, we measured the brain and plasma concentrations of these drugs. Oral administration of donepezil, tacrine, ENA-713 or TAK-147, caused a dose-dependent inhibition of brain and plasma cholinesterase activities. The ID 50 values of these compounds for brain cholinesterase activity were 6.3, 40.5, 7.2 and 26.8 μmol/kg, respectively. On the other hand, the ID 50 values for plasma cholinesterase activity were 89.0, >170, 9.7 and 51.2 μmol/kg, respectively. Thus, the ratios of the ID 50 (plasma/brain) were 14.1, >4.2, 1.3 and 1.9, respectively. Brain and plasma concentrations of donepezil, tacrine and TAK-147 increased dose-dependently. The ratios of the concentrations (brain/plasma) of these compounds were 6.1–8.4 for donepezil, 14.5–54.6 for tacrine and 7.0–20.6 for TAK-147. The values of 50% inhibitory concentration of these drugs in the brain were 0.42, 3.5 and 1.1 nmol/g, respectively. In contrast, the brain and plasma concentrations of ENA-713 at all doses, except the two highest doses, were below the quantification limit. These results suggest that orally administered donepezil satisfactorily penetrates into the brain and inhibits cholinesterase there, and that donepezil is a potent and selective inhibitor of brain cholinesterase in comparison with plasma cholinesterase in vivo.