Abstract
Dextromethorphan (DEM)-mediatedN-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.
Footnotes
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Send reprint requests to: Jules A. Desmeules, M.D., Division of Clinical Pharmacology, University Hospital, CH-1211 Geneva 14, Switzerland.
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↵1 Presented in part at the 98th Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, San Diego, California, March 1997.
- Abbreviations:
- DEM
- dextromethorphan
- NMDA
- N-methyl-d-aspartate
- DOR
- dextrorphan
- PINS
- pain intensity numerical scale
- PID
- pain intensity difference
- SPID
- sum of pain intensity difference
- PM
- poor metabolizer(s)
- EM
- extensive metabolizer(s)
- Qd
- quinidine sulfate
- Received January 12, 1998.
- Accepted August 26, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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