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-3-yl)methyl]-5,6-dimet hoxy-indan-1-one monohydrochloride: E2020: donepezil) is a potent and selec tive acetylcholinesterase inhibitor developed for the treatment of Alzheime r's disease. The present experiments were designed to compare the inhibitor y effects of orally administered donepezil and other cholinesterase inhibit ors, tacrine (9-amino-1,2,3,4-tetrahydroacridine hydrochloride), (S)-N-ethy l-3-[(1-dimethyl-amino)ethyl]-N-methyl-phenylcarbamate hydrogentartrate (EN A-713, rivastigmine) and 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetr ahydro-1H-1-benzazepin-8-yl)-1-propanone fumarate (TAK-147), on the choline sterase activity in the brain and plasma of rats. Moreover, in order to val idate the cholinesterase inhibition data, we measured the brain and plasma concentrations of these drugs. Oral administration of donepezil, tacrine, E NA-713 or TAK-147, caused a dose-dependent inhibition of brain and plasma c holinesterase activities. The ID50 values of these compounds for brain chol inesterase activity were 6.3, 40.5, 7.2 and 26.8 mu mol/kg, respectively. O n the other hand, the ID50 values for plasma cholinesterase activity were 8 9.0, > 170, 9.7 and 51.2 mu mol/kg, respectively. Thus, the ratios of the I D50 (plasma/brain) were 14.1, >4.2, 1.3 and 1.9, respectively. Brain and pl asma concentrations of donepezil, tacrine and TAK-147 increased dose-depend ently. The ratios of the concentrations (brain/plasma) of these compounds w ere 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 administe red donepezil satisfactorily penetrates into the brain and inhibits choline sterase there, and that donepezil is a potent and selective inhibitor of br ain cholinesterase in comparison with plasma cholinesterase in vivo. (C) 20 00 Elsevier Science B.V. All rights reserved.