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Measurement of CYP2D6 and CYP3A4 activity in vivo with dextromethorphan: sources of variability and predictors of adverse effects in 419 healthy subjects

  • Pharmacogenetics
  • Published:
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Abstract

Objective

Dextromethorphan (DEM) shares part of the adverse event profile of opioids and is widely used as a probe drug for CYP2D6 phenotyping and for the assessment of CYP2D6 activity. It has also been used to assess CYP3A4 activity. This study examined the influence of anthropometric variables, oral contraceptives, smoking habits, μ-opioid receptor and MDR1 genetic polymorphisms and components of the DEM ratios on the variability of CYP2D6 and CYP3A4 metabolic ratios and on the occurrence of adverse events following DEM administration.

Methods

This was a retrospective analysis of a database in 419 healthy subjects. CYP2D6 and CYP3A4 metabolic ratios were measured as the log of the ratios of the amount of DEM to the amount of dextrorphan (DOR) and of the amount of DEM to the amount of 3-methoxy-morphinan (MET) excreted in urine during a 12-h time period, respectively, following the oral administration of 80 mg of dextromethorphan hydrobromide. Logistic regression was performed to examine the factors associated with changes in metabolic ratios and with the occurrence of adverse events.

Results

The CYP2D6 metabolic ratio allowed identification of extensive and poor metabolizers of DEM. The CYP2D6 and CYP3A4 metabolic ratios were not strictly independent one from each other. Based on multivariate analysis, the CYP2D6 metabolic ratio was a stronger independent predictor of adverse events (p<0.0001) than the CYP2D6 phenotype (p=0.05). Anthropometric variables, oral contraceptives, smoking habits, μ-opioid receptor and MDR1 genetic polymorphisms did not significantly contribute to changes in metabolic ratios or to the occurrence of adverse events.

Conclusions

Dextromethorphan can be used for CYP2D6 phenotyping, but the CYP2D6 and CYP3A4 metabolic ratios are not strictly independent one from each other. The CYP2D6 metabolic ratio predicts adverse events to DEM as does CYP2D6 phenotype, and extensive metabolizer subjects are not protected against adverse events.

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Acknowledgements

We are indebted to Martine Lebot BSc. for assaying the dextromethorphan urine samples, to Liliane Dubert for preparing and processing the DNA samples, to Jean-Louis Démolis M.D. for his participation to the inclusion of the volunteers and to the staff of the Clinical Investigation Center for their enthusiastic and careful collection of the data.

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Authors and Affiliations

  1. INSERM – AP-HP, Clinical Investigation Center, CIC-9304, 75012, Paris, France

    Christian Funck-Brentano

  2. Department of Pharmacology, Pierre et Marie Curie University, 75012, Paris, France

    Christian Funck-Brentano, Céline Verstuyft, Célia Bornert, Laurent Becquemont & Jean-Marie Poirier

  3. AP-HP, Division of Clinical Pharmacology, Saint-Antoine Hospital, 75012, Paris, France

    Christian Funck-Brentano, Céline Verstuyft, Célia Bornert, Laurent Becquemont & Jean-Marie Poirier

  4. Department of Public Health, Pierre et Marie Curie University, 75012, Paris, France

    Pierre-Yves Boëlle

  5. INSERM, U444, 72012, Paris, France

    Pierre-Yves Boëlle

  6. Clinical Investigation Center, Saint-Antoine Hospital, 184 rue du Faubourg Saint-Antoine, 75571, Paris Cedex 12, France

    Christian Funck-Brentano

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  1. Christian Funck-Brentano
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  2. Pierre-Yves Boëlle
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Correspondence to Christian Funck-Brentano.

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This study was supported by a grant-in-aid from the Institut National de la Santé et de la Recherche Médicale and the Assistance Publique-Hôpitaux de Paris at the Clinical Investigation Center of Saint-Antoine University Hospital. The legal sponsor was the INSERM.

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Funck-Brentano, C., Boëlle, PY., Verstuyft, C. et al. Measurement of CYP2D6 and CYP3A4 activity in vivo with dextromethorphan: sources of variability and predictors of adverse effects in 419 healthy subjects. Eur J Clin Pharmacol 61, 821–829 (2005). https://doi.org/10.1007/s00228-005-0051-5

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  • DOI: https://doi.org/10.1007/s00228-005-0051-5

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