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Research ArticleArticle

Altered Plasma and Brain Disposition and Pharmacodynamics of Methadone in Abstinent Rats

María J. Garrido, Marta Valle, Rosario Calvo and Iñaki F. Trocóniz
Journal of Pharmacology and Experimental Therapeutics January 1999, 288 (1) 179-187;
María J. Garrido
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Marta Valle
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Rosario Calvo
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Iñaki F. Trocóniz
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Abstract

The pharmacokinetics and pharmacodynamics of methadone were investigated in control and abstinent rats. Minipumps filled with saline (control group) or saline-morphine (abstinent group) solutions were used to induce physical dependence. Solutions were delivered continuously by minipumps for 6 days. The physical dependence was evaluated 12 h after minipump removal by measuring specific withdrawal signs. Animals from the abstinent group showed clear withdrawal signs such as hostility on handling and weight loss. Plasma and brain disposition and pharmacodynamics of methadone were evaluated after a 0.35 mg/kg i.v. bolus dose administered 12 h after minipump removal. Plasma clearance, distribution clearance, and volume of distribution at steady-state were significantly decreased (P < 0.05) in the abstinent group. Plasma levels of α1-acid glycoprotein and plasma protein binding were significantly increased (P < 0.05) in the abstinent group. The estimates of pharmacokinetic parameters based on unbound plasma concentrations did not differ between groups, with the sole exception of the unbound apparent volume of distribution. The access of methadone to the brain was significantly faster (P < 0.05) in the abstinent group, although the extent of distribution in the brain was diminished in comparison with the control group. Analgesia recorded with tail-flick was used as the pharmacodynamic endpoint. Analgesic response and effect compartment concentrations of methadone were related by the sigmoidalEmax model. Estimates ofC50 [steady-state plasma concentrations eliciting half of maximum effect (Emax)]] based on unbound concentrations did not differ between groups. On the other hand, the estimate of Emax had decreased by 65% in the abstinent group.

Footnotes

  • Send reprint requests to: Marı́a J. Garrido, Departamento de Farmacologı́a, Facultad de Medicina, Universidad del Paı́s Vasco, Lejona 48940, Vizcaya, Spain. E-mail:kfbgacim{at}lg.ehu.es.

  • 1 This work was supported by Grant from Dpto. Educación, Universidades e Investigación, Gobierno Vasco.

  • Abbreviations:
    C
    total plasma concentration of methadone
    Cu
    unbound plasma concentration of methadone
    Cbrain
    total brain concentration of metadone
    C50, steady-state plasma concentrations eliciting half of maximum effect (Emax)
    pk/pd,pharmacokinetic-pharmacodynamic
    fu
    unbound fraction
    AAG
    α1-acid glycoprotein
    %MPR
    percentage of maximum possible response
    • Received March 11, 1998.
    • Accepted July 22, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 288 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 288, Issue 1
1 Jan 1999
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Research ArticleArticle

Altered Plasma and Brain Disposition and Pharmacodynamics of Methadone in Abstinent Rats

María J. Garrido, Marta Valle, Rosario Calvo and Iñaki F. Trocóniz
Journal of Pharmacology and Experimental Therapeutics January 1, 1999, 288 (1) 179-187;

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Research ArticleArticle

Altered Plasma and Brain Disposition and Pharmacodynamics of Methadone in Abstinent Rats

María J. Garrido, Marta Valle, Rosario Calvo and Iñaki F. Trocóniz
Journal of Pharmacology and Experimental Therapeutics January 1, 1999, 288 (1) 179-187;
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