Scientific article
Open access

Contribution of cytochrome P-4502D6 phenotype to the neuromodulatory effects of dextromethorphan

Published inThe Journal of pharmacology and experimental therapeutics, vol. 288, no. 2, p. 607-612
Publication date1999

Dextromethorphan (DEM)-mediated N-methyl-D-aspartate receptor blockade may result from an action of unchanged DEM or its active metabolite, dextrorphan (DOR). In humans, DEM is metabolized into DOR by the polymorphic enzyme CYP2D6. We therefore investigated the impact of quinidine (Qd), a selective inhibitor of CYP2D6, on DEM disposition and the contribution of CYP2D6 phenotype on DEM antinociceptive and neuromodulatory effects. Using a randomized, double-blind, crossover, placebo-controlled design, healthy volunteers (n = 7) received Qd (50 mg Qd sulfate orally) or a placebo and, 12 h later, either DEM (50 mg DEM hydrobromide orally) or a placebo. DEM and DOR pharmacodynamics were assessed for their antinociceptive and neuromodulatory effects. Antinociceptive effects were assessed over 4 h by subjective pain threshold and RIII nociceptive reflex (RIII) monitoring. Neuromodulatory effects were studied using the primary and secondary hyperalgesia induced by the topical application of capsaicin. Two of seven subjects were genotypic CYP2D6 PM. Pretreatment of EM by Qd suppressed DOR formation and increased the plasma level of DEM to the levels of poor metabolizers. In poor metabolizers, DEM induced a significant increase in objective (+45%) and subjective (+35%) pain thresholds. In extensive metabolizers, only a slight and short-lasting increase in the subjective threshold was observed, whereas no effect was seen on the objective threshold. DEM modulates secondary hyperalgesia compared with DOR. The CYP2D6 phenotype affects the disposition of DEM and the production of the active metabolite DOR. The impact of the CYP2D6 phenotype is of major importance for the spinal antinociceptive and neuromodulatory effects of DEM.

  • Adult
  • Cross-Over Studies
  • Cytochrome P-450 CYP2D6/metabolism/physiology
  • Cytochrome P-450 CYP2D6 Inhibitors
  • Dextromethorphan/pharmacokinetics/pharmacology
  • Enzyme Inhibitors/pharmacology
  • Excitatory Amino Acid Antagonists/pharmacokinetics/pharmacology
  • Female
  • Humans
  • Hyperalgesia/drug therapy
  • Male
  • Neurotransmitter Agents/pharmacokinetics/pharmacology
  • Nociceptors/drug effects
  • Pain Threshold/drug effects
  • Phenotype
  • Placebos
  • Quinidine/pharmacology
  • Tissue Distribution
Citation (ISO format)
DESMEULES, Jules Alexandre et al. Contribution of cytochrome P-4502D6 phenotype to the neuromodulatory effects of dextromethorphan. In: The Journal of pharmacology and experimental therapeutics, 1999, vol. 288, n° 2, p. 607–612.
Main files (1)
Article (Published version)
ISSN of the journal0022-3565

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