Vol. 291, Issue 3, 1220-1226, December 1999

Spontaneous Locomotor Activity and Pharmacokinetics of Intravenous Methamphetamine and Its Metabolite Amphetamine in the Rat¹

Gilles J. Rivière, Kelly A. Byrnes, W. Brooks Gentry and S. Michael Owens

Departments of Pharmacology and Toxicology (G.J.R., K.A.B., S.M.O.) and Anesthesiology (W.B.G.), College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas

The purpose of these studies was to better understand the behavioral effects and pharmacokinetics of an i.v. bolus dose of (+)-methamphetamine [(+)-METH] in a rat model of (+)-METH abuse. We characterized the behavioral effects after increasing (+)-METH doses (0.1, 0.3, and 1.0 mg/kg) and the pharmacokinetics of (+)-METH (and its metabolite (+)-amphetamine [(+)-AMP)]) at the lowest and highest of these doses in adult male Sprague-Dawley rats. The doses and route of administration were selected to mimic aspects of human use on a dose/body weight basis. Although the 0.1 mg/kg dose did not cause statistically significant increases in locomotor activity compared with saline controls, the higher doses (0.3 and 1.0 mg/kg) caused statistically significant increases in locomotor activity (p < .05), which lasted for up to 3 h at the highest dose. After the 1.0 mg/kg dose, the volume of distribution at steady state was 9.0 liters/kg, the total clearance was 126 ml/min/kg, and the average distribution and elimination half-lives were 9.2 and 63.0 min, respectively. Because the pharmacokinetic values after the 0.1 mg/kg dose were not different from those after the 1.0 mg/kg dose, the pharmacokinetics of (+)-METH were considered to be independent of the dose over this 10-fold range. (+)-AMP serum concentrations after the 1.0 mg/kg dose peaked from 10 to 30 min, and exhibited a T_1/2z of 98.5 min. The statistically longer T_1/2z of (+)-AMP (p < .05) suggested that the (+)-AMP terminal elimination rate and not the (+)-AMP metabolic formation rate is the rate-limiting step in (+)-AMP elimination following i.v. (+)-METH dosing.