Spontaneous locomotor activity and pharmacokinetics of intravenous methamphetamine and its metabolite amphetamine in the rat

The purpose of these studies was to better understand the behavioral effect s and pharmacokinetics of an i.v. bolus dose of (+)-methamphetamine [(+)-ME TH] in a rat model of (+)-METH abuse. We characterized the behavioral effec ts after increasing (+)-METH doses (0.1, 0.3, and 1.0 mg/kg) and the pharma cokinetics of (+)-METH (and its metabolite (+)-amphetamine [(+)-AMP)]) at t he 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 sal ine controls, the higher doses (0.3 and 1.0 mg/kg) caused statistically sig nificant 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 distributi on 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 pharmacoki netics 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-1/2 lambda z of 98.5 min. The statist ically longer T-1/2 lambda z of (+)-AMP (p < .05) suggested that the (+)-AM P terminal elimination rate and not the (+)-AMP metabolic formation rate is the rate-limiting step in (+)-AMP elimination following i.v. (+)-METH dosi ng.