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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Pharmacokinetic/Pharmacodynamic Modeling of the Antinociceptive Effects of (+)-Tramadol in the Rat: Role of Cytochrome P450 2D Activity

Marı́a J. Garrido, Onintza Sayar, Cristina Segura, Javier Rapado, Marı́a Carmen Dios-Viéitez, Marı́a Jesús Renedo and Iñaki F. Trocóniz
Journal of Pharmacology and Experimental Therapeutics May 2003, 305 (2) 710-718; DOI: https://doi.org/10.1124/jpet.102.047779
Marı́a J. Garrido
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Onintza Sayar
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Cristina Segura
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Javier Rapado
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Marı́a Carmen Dios-Viéitez
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Marı́a Jesús Renedo
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Iñaki F. Trocóniz
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Abstract

In this study the role of cytochrome P450 2D (CYP2D) in the pharmacokinetic/pharmacodynamic relationship of (+)-tramadol [(+)-T] has been explored in rats. Male Wistar rats were infused with (+)-T in the absence of and during pretreatment with a reversible CYP2D inhibitor quinine (Q), determining plasma concentrations of Q, (+)-T, and (+)-O-demethyltramadol [(+)-M1], and measuring antinociception. Pharmacokinetics of (+)-M1, but not (+)-T, was affected by Q pretreatment: early after the start of (+)-T infusion, levels of (+)-M1 were significantly lower (P < 0.05). However, at later times during Q infusion those levels increased continuously, exceeding the values found in animals that did not receive the inhibitor. These results suggest that CYP2D is involved in the formation and elimination of (+)-M1. In fact, results from another experiment where (+)-M1 was given in the presence and in absence of Q showed that (+)-M1 elimination clearance (CLME0) was significantly lower (P < 0.05) in animals receiving Q. Inhibition of both (+)-M1 formation clearance (CLM10) and CLME0 were modeled by an inhibitoryEMAX model, and the estimates (relative standard error) of the maximum degree of inhibition (EMAX) and IC50, plasma concentration of Q eliciting half of EMAXfor CLM10 and CLME0, were 0.94 (0.04), 97 (0.51) ng/ml, and 48 (0.42) ng/ml, respectively. The modeling of the time course of antinociception showed that the contribution of (+)-T was negligible and (+)-M1 was responsible for the observed effects, which depend linearly on (+)-M1 effect site concentrations. Therefore, the CYP2D activity is a major determinant of the antinociception elicited after (+)-T administration.

Footnotes

  • This work was supported by Grünenthal GmbH (Aachen, Germany).

  • DOI: 10.1124/jpet.102.047779

  • Abbreviations:
    (+)-
    (−)-M1, (+)-, (−)-O-demethyltramadol
    (+)-
    (−)-T, (+)-, (−)-tramadol
    Ce
    concentration in the effect site
    CLD
    distribution clearance
    CLM10
    initial (+)-M1 formation clearance
    CLM2
    clearance representing other routes of (+)-T elimination
    CLME0
    initial apparent (+)-M1 elimination clearance
    CYP2D
    D1, D6, cytochromes P450 2D, 2D1, and 2D6
    E0
    baseline latency
    HPLC
    high-performance liquid chromatography
    ke0
    first-order rate constant governing drug distribution from plasma to the effect site
    pk/pd
    pharmacokinetic/pharmacodynamic
    Q
    quinine
    RSE
    relative standard error
    V
    apparent volume of distribution of the central compartment
    VT
    apparent volume of distribution outside the central compartment
    Z
    shape of the Weibull probability distribution
    • Received December 5, 2002.
    • Accepted January 31, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 305 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 305, Issue 2
1 May 2003
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Pharmacokinetic/Pharmacodynamic Modeling of the Antinociceptive Effects of (+)-Tramadol in the Rat: Role of Cytochrome P450 2D Activity

Marı́a J. Garrido, Onintza Sayar, Cristina Segura, Javier Rapado, Marı́a Carmen Dios-Viéitez, Marı́a Jesús Renedo and Iñaki F. Trocóniz
Journal of Pharmacology and Experimental Therapeutics May 1, 2003, 305 (2) 710-718; DOI: https://doi.org/10.1124/jpet.102.047779

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Pharmacokinetic/Pharmacodynamic Modeling of the Antinociceptive Effects of (+)-Tramadol in the Rat: Role of Cytochrome P450 2D Activity

Marı́a J. Garrido, Onintza Sayar, Cristina Segura, Javier Rapado, Marı́a Carmen Dios-Viéitez, Marı́a Jesús Renedo and Iñaki F. Trocóniz
Journal of Pharmacology and Experimental Therapeutics May 1, 2003, 305 (2) 710-718; DOI: https://doi.org/10.1124/jpet.102.047779
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