Pharmacokinetics and Drug Disposition
Clinical Pharmacology & Therapeutics (1996) 60, 276–282; doi:
Clinical pharmacokinetics of arecoline in subjects with Alzheimer's disease*
Sanjay Asthana MD1, Nigel H. Greig PhD1, Harold W. Holloway BS1, Kathleen C. Raffaele PhD1,†, Annamaria Berardi PhD1,‡, Mark B. Schapiro MD1, Stanley I. Rapoport MD1 and Timothy T. Soncrant MD1
1Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, Md., USA
Correspondence: Sanjay Asthana, MD, GRECC (182 B), VA Medical Center, American Lake, Tacoma, WA 98493.
†Current address: Food and Drug Administration, HFS-227, 200 C St. SW, Washington, DC 20204.
‡Current address: Harvard University, Department of Psychology, 33 Kirkland St., Cambridge, MA 02138.
*Preliminary results of this study were presented at the Ninety-third Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, Orlando, Fla., March 18–20, 1992.
Received 5 January 1996; Accepted 23 April 1996.
Abstract
Objective: To study the pharmacokinetics and pharmacodynamics of intravenously administered arecoline in subjects with Alzheimer's disease.
Methods: Plasma arecoline concentrations were measured during and after high-dose (i.e., 5 mg intravenously over 30 minutes) and up to 2 weeks of continuous multiple-dose steady-state intravenous infusions of arecoline in 15 subjects with mild to moderate Alzheimer's disease. During multiple-dose infusions, the dose of arecoline was escalated from 0.5 to 40 mg/day. Psychometric tests were administered at baseline and every other dose to determine an "optimal dose" for each subject. This dose then was administered for 1 week using a randomized, placebo-controlled, double-blind, crossover design. Plasma drug concentrations were measured by GC-MS.
Results: The optimal dose of arecoline varied fourfold across subjects (4 mg/day, n = 6; 16 mg/day, n = 3) with mean plasma half-lives of 0.95 
0.54 and 9.3 4.5 (SD) minutes. Clearance and volume of distribution were 13.6 5.8 L/min and 205 170 (SD) L, respectively. At the dose that optimized memory, the mean plasma level was 0.31 0.14 (SD) ng/ml, and it predicted the optimal dose in all subjects.
Conclusions: Because optimal dose variation is due to differing plasma kinetics, the plasma arecoline level measured at a single infusion rate can be used to choose the optimal dose for memory enhancement in patients with Alzheimer's disease.
