Estimation of plasma IC50 of donepezil for cerebral acetylcholinesterase inhibition in patients with Alzheimer disease using positron emission tomography.
OBJECTIVE
Estimate the value of in vivo plasma IC50 of donepezil, the concentration of donepezil in plasma that inhibits brain acetylcholinesterase (AChE) activity by 50% at the steady-state conditions of donepezil between the plasma and the brain.


METHODS
N-[C] methylpiperidin-4-yl acetate ([C]MP4A) positron emission tomography was performed in 16 patients with probable Alzheimer disease (AD) before and during the treatment of donepezil (5 mg/day) with a mean interval of 5.3 months. The plasma IC50 value of donepezil was estimated from plasma donepezil concentrations and cerebral cortical mean AChE inhibition rates measured by positron emission tomography, using one-parameter model.


RESULTS
Donepezil reduced AChE activity uniformly in the cerebral cortex compared with the baseline in each AD patient, and the mean reduction rate in the cerebral cortex was 34.6%. The donepezil concentrations in the plasma ranged from 18.5 to 43.9 ng/mL with a mean of 28.9 +/- 7.3 ng/mL. The plasma IC50 value was estimated to be 53.6 +/- 4.0 ng/mL.


CONCLUSIONS
Once the plasma IC50 of donepezil is determined, the brain AChE inhibition rate could be estimated from the plasma concentration of donepezil in each subject based on the plasma IC50. Now that the mean donepezil concentrations in the plasma, when the patients took 5 mg/day, remained 28.9 ng/mL, approximately half of the plasma IC50, higher dose of donepezil might provide further benefits for patients with AD. This technique can be also applied to measure the in vivo plasma IC50 of other cholinesterase inhibitors such as rivastigmine and galantamine.
Ota
Tsuneyoshi
T
Department of Molecular Probe, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan. ota@juntendo.ac.jp
Shinotoh
Hitoshi
H
Fukushi
Kiyoshi
K
Kikuchi
Tatsuya
T
Sato
Koichi
K
Tanaka
Noriko
N
Shimada
Hitoshi
H
Hirano
Shigeki
S
Miyoshi
Michie
M
Arai
Heii
H
Suhara
Tetsuya
T
Irie
Toshiaki
T
D000110:Acetylcholinesterase / Q000187:drug effects*; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism*; D002540:Cerebral Cortex / Q000000981:diagnostic imaging / Q000187:drug effects*; D002800:Cholinesterase Inhibitors / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D000077265:Donepezil; D005260:Female; D006801:Humans; D007189:Indans / Q000097:blood* / Q000494:pharmacology* / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000097:blood* / Q000494:pharmacology* / Q000627:therapeutic use; D049268:Positron-Emission Tomography / Q000379:methods*
D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D000077265:Donepezil; D000110:Acetylcholinesterase