Abstract
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 aT1/2λz of 98.5 min. The statistically longer T1/2λz 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.
Footnotes
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Send reprint requests to: Dr. S. Michael Owens, Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, 4301 W. Markham, Slot 611, Little Rock, AR 72205. E-mail:owenssamuelm{at}exchange.uams.edu or Dr. W. Brooks Gentry, Dept. of Anesthesiology, University of Arkansas for Medical Sciences, 4301 W. Markham, Slot 515, Little Rock, AR 72205. E-mail:gentrywilliamb{at}exchange.uams.edu
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↵1 This work was supported by National Institute on Drug Abuse Grants R01 DA11560 (to S.M.O.), K08 DA0339 (to W.B.G.), and F31 DA05939 (to K.A.B.).
- Abbreviations:
- (+)-METH
- (+)-methamphetamine
- CNS
- central nervous system
- (+)-AMP
- (+)-amphetamine
- AUC
- area under the serum concentration versus time curve
- ClNR
- nonrenal clearance
- ClR
- renal clearance
- ClT
- total body clearance
- λz
- terminal elimination rate constant
- Vdss
- volume of distribution at steady state
- T1/2λ1
- distribution half-life
- T1/2λz
- terminal elimination half-life
- Received May 28, 1999.
- Accepted August 31, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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