Clinical pharmacokinetics of physostigmine in patients with Alzheimer's disease.
OBJECTIVE
To study the pharmacokinetic and pharmacodynamic properties of physostigmine in subjects with Alzheimer's disease.


METHODS
Plasma physostigmine concentration and butyrylcholinesterase inhibition were measured in blood samples collected during and after a single high-dose (1 to 1.5 mg for 45 to 60 minutes) and a sustained low-dose steady-state intravenous infusion in nine subjects with Alzheimer's disease. Escalating doses (0.5 to 25 mg/day) were administered during a 2-week period. A dose (2 to 12 mg/day) that optimized cognition in each subject was identified and then administered in a randomized, double-blind, placebo-controlled crossover design for 1 week.


RESULTS
The elimination half-life of physostigmine was 16.4 +/- 3.2 (SE) minutes. Clearance and volume of distribution were 7.7 +/- 0.9 (SE) L/min and 2.4 +/- 0.6 (SE) L/kg, respectively. Butyrylcholinesterase inhibition half-life was 83.7 +/- 5.2 (SE) minutes. During sustained steady-state infusion, plasma physostigmine concentration (r = 0.95) and butyrylcholinesterase inhibition (r = 0.99) were linearly correlated with the dose. In five cognitive responders, the memory enhancement was significantly correlated (r = 0.86; p < 0.05) with butyrylcholinesterase inhibition.


CONCLUSIONS
These results showed that, in cognitive responders, memory enhancement by physostigmine in Alzheimer's disease is correlated directly to the magnitude of plasma cholinesterase inhibition. Furthermore, during single-dose conditions, the dynamic half-life is five-fold longer than the kinetic half-life.
Asthana
S
S
Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, Md, USA.
Greig
N H
NH
Hegedus
L
L
Holloway
H H
HH
Raffaele
K C
KC
Schapiro
M B
MB
Soncrant
T T
TT
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D003071:Cognition / Q000187:drug effects; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007206:Individuality; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D010830:Physostigmine / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology
D002800:Cholinesterase Inhibitors; D010830:Physostigmine