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Semi-mechanistic Pharmacokinetic/Pharmacodynamic Modelling of the Antinociceptive Response in the Presence of Competitive Antagonism: The Interaction Between Tramadol and its Active Metabolite on μ-Opioid Agonism and Monoamine Reuptake Inhibition, in the Rat

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Abstract

Purpose

To establish a semi-mechanistic pharmacokinetic/pharmacodynamic (pk/pd) model for racemic tramadol (T) integrating all the components with a significant contribution to T effects in rats, using cold allodynia in the Bennett model of neuropathic pain.

Methods

Male Sprague-Dawley rats (n=53) were randomly allocated in six groups receiving saline, racemic T (5 mg/kg), RR-T (5 mg/kg), SS-T (5 mg/kg), RR-O-demethyltramadol [RR-M1 (1 mg/kg)] or SS-M1 (30 mg/kg) in two h intravenous infusion.

Results

The μ-opioid effects of RR-M1 (ERR-M1) were described with an effect compartment model. Contribution to analgesic response of RR-T resulted negligible. The monoamine re-uptake inhibition effects (E SS-M1,T) were modelled as an indirect response model incorporating a competitive interaction between SS-T and SS-M1. ERR-M1 and E SS-M1,T were finally considered as a two independent stimuli converging into a single and common antinoceptive stimulus. The estimates of the steady-state plasma concentrations eliciting half of maximum response for RR-M1, SS-T, and SS-M1 were 20.2, 230, and 869 ng/ml, respectively. RR-M1 is the main active component, but SS-T having a significant contribution.

Conclusion

Cold allodynia in the Bennett model has proven an adequate experimental set up to develop complex pk/pd models in analgesia involving different mechanisms of action.

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Abbreviations

E RR-M1, E SS-M1, E SS-T, E SS-M1,T, E RRSS :

0-1 normalized antinociceptive stimuli elicited by RR-M1, SS-M1, the combination of SS-T and SS-M1, and the interaction between the μ-opioid and monoamine re-uptake inhibition mechanisms, respectively

k e0 :

first order rate constant governing the equilibrium in the distribution between plasma and biophase

k in, and k out are the zero:

and first order rate constants of release and re-uptake of noradrenaline, respectively

M1:

O-demethyltramadol

RR-M1:

RR-O-demethyltramadol

RR-T:

RR-Tramadol

SS-M1:

SS-O-demethyltramadol

SS-T:

SS-Tramadol

T:

racemic tramadol

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Acknowledgments

We like to thank Manuela Graff, Elke Schumacher, Johanna Korioth and Carolin Koll for excellent technical support. The contribution of Norbert Bromet, Biotec Centre (Orleans, France) to the bioanalytical determination of drug concentrations in plasma is greatly appreciated.

Author information

Authors and Affiliations

  1. Department of Pharmacokinetics, Grünenthal GmbH, 52078, Aachen, Germany

    Horst Beier & Dirk Kasel

  2. Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Apartado 177, Pamplona, 31080, Spain

    María J. Garrido & Iñaki F. Trocóniz

  3. Department of Pharmacology, Grünenthal GmbH, 52078, Aachen, Germany

    Thomas Christoph

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  1. Horst Beier
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  2. María J. Garrido
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Correspondence to Iñaki F. Trocóniz.

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Beier, H., Garrido, M.J., Christoph, T. et al. Semi-mechanistic Pharmacokinetic/Pharmacodynamic Modelling of the Antinociceptive Response in the Presence of Competitive Antagonism: The Interaction Between Tramadol and its Active Metabolite on μ-Opioid Agonism and Monoamine Reuptake Inhibition, in the Rat. Pharm Res 25, 1789–1797 (2008). https://doi.org/10.1007/s11095-007-9489-8

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