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Research ArticleNEUROPHARMACOLOGY

Pharmacokinetic-Pharmacodynamic Modeling of the Antinociceptive Effects of Main Active Metabolites of Tramadol, (+)-O-Desmethyltramadol and (−)-O-Desmethyltramadol, in Rats

Marta Valle, María J. Garrido, Juan M. Pavón, Rosario Calvo and Iñaki F. Trocóniz
Journal of Pharmacology and Experimental Therapeutics May 2000, 293 (2) 646-653;
Marta Valle
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María J. Garrido
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Juan M. Pavón
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Rosario Calvo
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Iñaki F. Trocóniz
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Abstract

The pharmacokinetics and pharmacodynamics of the two main metabolites of tramadol, (+)-O-desmethyltramadol and (−)-O-desmethyltramadol, were studied in rats. Pharmacodynamic endpoints evaluated were respiratory depression, measured as the change in arterial blood pCO2, pO2, and pH levels; and antinociception, measured by the tail-flick technique. The administration of 10 mg/kg (+)-O-desmethyltramadol in a 10-min i.v. infusion significantly altered pCO2, pO2, and pH values in comparison with baseline and lower-dose groups (P < .05). However, 2 mg/kg administered in a 10-min i.v. infusion was enough to achieve 100% antinociception without respiratory depression. Moreover, the β-funaltrexamine pretreatment completely eliminated the antinociception of the 2-mg/kg dose, suggesting that such an effect is due to μ-opioid receptor activation. To describe and adequately characterize the in vivo antinociceptive effect of the drug, (+)-O-desmethyltramadol was given at different infusion rates of varying lengths (10–300 min). Pharmacokinetics was best described by a two-compartmental model. The time course of response was described using an effect compartment associated with a linear pharmacodynamic model. The estimates of the slope of the effect versus concentration relationship were significantly decreased (P < .05) as the length of infusion was increased, suggesting the development of tolerance. Doses of up to 8 mg/kg (−)-O-desmethyltramadol given in 10-min i.v. infusion did not elicit either antinociception in the tail-flick test or respiratory effects. These in vivo results are in accordance with the opiate and nonopiate properties reported for these compounds in several in vitro studies.

Footnotes

  • Send reprint requests to: Iñaki F. Trocóniz PhD, Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Navarra, Pamplona 31080, Spain. E-mail:itroconiz{at}unav.es.

  • ↵1 This work was supported by a grant from the University of Basque Country (026, EB 231/96). M.V. was supported by a fellowship from the University of Basque Country.

  • ↵2 Current address: Department of Biopharmaceutical Sciences, School of Pharmacy, University of California, San Francisco, CA.

  • ↵3 Current address: Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Navarra, Pamplona, Spain.

  • Abbreviations:
    %MPE
    percentage of maximum possible effect
    M1
    O-desmethyltramadol
    β-FNA
    β-funaltrexamine
    pk
    pharmacokinetic
    pd
    pharmacodynamic
    NA
    noradrenaline
    Cl
    total plasma clearance
    c.v.
    coefficients of variation
    • Received August 31, 1999.
    • Accepted January 31, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 293 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 293, Issue 2
1 May 2000
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Research ArticleNEUROPHARMACOLOGY

Pharmacokinetic-Pharmacodynamic Modeling of the Antinociceptive Effects of Main Active Metabolites of Tramadol, (+)-O-Desmethyltramadol and (−)-O-Desmethyltramadol, in Rats

Marta Valle, María J. Garrido, Juan M. Pavón, Rosario Calvo and Iñaki F. Trocóniz
Journal of Pharmacology and Experimental Therapeutics May 1, 2000, 293 (2) 646-653;

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Research ArticleNEUROPHARMACOLOGY

Pharmacokinetic-Pharmacodynamic Modeling of the Antinociceptive Effects of Main Active Metabolites of Tramadol, (+)-O-Desmethyltramadol and (−)-O-Desmethyltramadol, in Rats

Marta Valle, María J. Garrido, Juan M. Pavón, Rosario Calvo and Iñaki F. Trocóniz
Journal of Pharmacology and Experimental Therapeutics May 1, 2000, 293 (2) 646-653;
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