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Research ArticleArticle

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

Gilles J. Rivière, Kelly A. Byrnes, W. Brooks Gentry and S. Michael Owens
Journal of Pharmacology and Experimental Therapeutics December 1999, 291 (3) 1220-1226;
Gilles J. Rivière
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Kelly A. Byrnes
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W. Brooks Gentry
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S. Michael Owens
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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

  • 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

  • ↵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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Journal of Pharmacology and Experimental Therapeutics: 291 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 291, Issue 3
1 Dec 1999
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Research ArticleArticle

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

Gilles J. Rivière, Kelly A. Byrnes, W. Brooks Gentry and S. Michael Owens
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 1220-1226;

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Research ArticleArticle

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

Gilles J. Rivière, Kelly A. Byrnes, W. Brooks Gentry and S. Michael Owens
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 1220-1226;
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