Mixed-effect circadian rhythm model for human erythrocyte acetylcholinesterase activity--application to the proof of concept of cholinesterase inhibition by acorn extract in healthy subjects with galantamine as positive control.
OBJECTIVE
The aim of this study was to develop a non-linear mixed effect circadian rhythm model of acetylcholinesterase (AChE) activity variation and to evaluate the inhibitory effect of acorn extract (2 g) and galantamine (16 mg), used as positive control, on human AChE in red blood cells (RBC).


METHODS
This was an open-label, randomized, three-way crossover study involving 12 healthy subjects who received one of the treatments in each study period: no treatment, acorn extract, and galantamine. RBC AChE activity was measured in peripheral blood samples collected at 0 (pre-dose), 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16 and 24 h post-dose administration. Non-linear mixed effect modeling was performed using NONMEM (ver. 7.0).


RESULTS
The circadian variation of AChE activity was best described using two mixed effect cosine functions, with periods of 24 and 12 h, respectively. When the inhibitory effect terms were added, the model was significantly improved for both acorn extract and galantamine. In terms of the effect, a 2-g single dose of acorn extract showed AChE inhibition (about 5%) similar to that of a 16-mg single dose of galantamine, in the first 24 h after administration.


CONCLUSIONS
Based on the very pronounced inter- and intra-day variation in AChE activity in RBC, we conclude that the model-based approach is essential for the proof of concept and quantitation of AChE inhibition in human subjects.
Department of Pharmacology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Seunghoon
S
Han
Jongtae
J
Lee
Sangil
S
Jeon
Taegon
T
Hong
Dong-Seok
DS
Yim
D000110:Acetylcholinesterase / Q000097:blood*; D000328:Adult; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D002940:Circadian Rhythm; D018592:Cross-Over Studies; D004912:Erythrocytes / Q000201:enzymology*; D058851:GPI-Linked Proteins / Q000097:blood; D005702:Galantamine / Q000494:pharmacology; D006801:Humans; D008954:Models, Biological; D018697:Nootropic Agents / Q000494:pharmacology; D009754:Nuts / Q000737:chemistry; D010936:Plant Extracts / Q000494:pharmacology*; D029963:Quercus / Q000737:chemistry*; D055815:Young Adult
D002800:Cholinesterase Inhibitors; D058851:GPI-Linked Proteins; D018697:Nootropic Agents; D010936:Plant Extracts; D005702:Galantamine; C548244:ACHE protein, human; D000110:Acetylcholinesterase