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

Oestreicher, M K
Published in Journal of Pharmacology and Experimental Therapeutics. 1999, vol. 288, no. 2, p. 607-612
Abstract 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.
Keywords AdultCross-Over StudiesCytochrome P-450 CYP2D6/metabolism/physiologyCytochrome P-450 CYP2D6 InhibitorsDextromethorphan/pharmacokinetics/pharmacologyEnzyme Inhibitors/pharmacologyExcitatory Amino Acid Antagonists/pharmacokinetics/pharmacologyFemaleHumansHyperalgesia/drug therapyMaleNeurotransmitter Agents/pharmacokinetics/pharmacologyNociceptors/drug effectsPain Threshold/drug effectsPhenotypePlacebosQuinidine/pharmacologyTissue Distribution
PMID: 9918565
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Research group Groupe Desmeules Jules (pharmacologie/toxicologie) (567)
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DESMEULES, Jules Alexandre et al. Contribution of cytochrome P-4502D6 phenotype to the neuromodulatory effects of dextromethorphan. In: Journal of Pharmacology and Experimental Therapeutics, 1999, vol. 288, n° 2, p. 607-612. https://archive-ouverte.unige.ch/unige:90115

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Deposited on : 2016-12-08

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