CLINICAL PHARMACOKINETICS OF PHYSOSTIGMINE IN PATIENTS WITH ALZHEIMERS-DISEASE

Objective: To study the pharmacokinetic and pharmacodynamic properties of physostigmine in subjects with Alzheimer's disease. Methods: Plasm a physostigmine concentration and butyrylcholinesterase inhibition wer e measured in blood samples collected during and after a single high-d ose (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 subj ect was identified and then administered in a randomized, double-blind , placebo-controlled crossover design for 1 week. Results: The elimina tion half-life of physostigmine was 16.4 +/- 3.2 (SE) minutes. Clearan ce and volume of distribution were 7.7 +/- 0.9 (SE) L/min and 2.4 +/- 0.6 (SE) L/kg, respectively. Butyrylcholinesterase inhibition half-lif e was 83.7 +/- 5.2 (SE) minutes. During sustained steady-state infusio n, plasma physostigmine concentration (r = 0.95) and butyrylcholineste rase inhibition (r = 0.99) were linearly correlated with the dose. In five cognitive responders, the memory enhancement was significantly co rrelated (r = 0.86; p < 0.05) with butyrylcholinesterase inhibition. C onclusions: These results showed that, in cognitive responders, memory enhancement by physostigmine in Alzheimer's disease is correlated dir ectly to the magnitude of plasma cholinesterase inhibition, Furthermor e, during single-dose conditions, the dynamic half-life is five-fold l onger than the kinetic half-life.