Donepezil is a potent, selective inhibitor of acetylcholinesterase, which is 
used for the treatment of Alzheimer's disease. Whole-cell patch-clamp technique 
and Western blot analyses were used to study the effects of donepezil on the 
human ether-a-go-go-related gene (hERG) channel. Donepezil inhibited the tail 
current of the hERG in a concentration-dependent manner with an IC50 of 1.3 μM. 
The metabolites of donepezil, 6-ODD and 5-ODD, inhibited the hERG currents in a 
similar concentration-dependent manner; the IC50 values were 1.0 and 1.5 μM, 
respectively. A fast drug perfusion system demonstrated that donepezil 
interacted with both the open and inactivated states of the hERG. A fast 
application of donepezil during the tail currents inhibited the open state of 
the hERG in a concentration-dependent manner with an IC50 of 2.7 μM. Kinetic 
analysis of donepezil in an open state of the hERG yielded blocking and 
unblocking rate constants of 0.54 µM(-1)s(-1) and 1.82 s(-1), respectively. The 
block of the hERG by donepezil was voltage-dependent with a steep increase 
across the voltage range of channel activation. Donepezil caused a reduction in 
the hERG channel protein trafficking to the plasma membrane at low 
concentration, but decreased the channel protein expression at higher 
concentrations. These results suggest that donepezil inhibited the hERG at a 
supratherapeutic concentration, and that it did so by preferentially binding to 
the activated (open and/or inactivated) states of the channels and by inhibiting 
the trafficking and expression of the hERG channel protein in the plasma 
membrane.