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Effect of the inhibition of CYP3A4 or CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

The main metabolic pathways of oxycodone, a potent opioid analgetic, are N-demethylation (CYP3A4) to inactive noroxycodone and O-demethylation (CYP2D6) to active oxymorphone. We performed a three-way, placebo-controlled, double-blind cross-over study to assess the pharmacokinetic and pharmacodynamic consequences of drug interactions with oxycodone.

Methods

The 12 participants (CYP2D6 extensive metabolizers) were pre-treated with placebo, ketoconazole or paroxetine before oral oxycodone ingestion (0.2 mg/kg).

Results

Pre-treatment with ketoconazole increased the AUC for oxycodone 2- to 3-fold compared with placebo or paroxetine. In combination with placebo, oxycodone induced the expected decrease in pupil diameter. This decrease was accentuated in the presence of ketoconazole, but blunted by paroxetine. In comparison to pre-treatment with placebo, ketoconazole increased nausea, drowsiness, and pruritus associated with oxycodone. In contrast, the effect of pre-treatment with paroxetine on the above-mentioned adverse events was not different from that of placebo. Ketoconazole increased the analgetic effect of oxycodone, whereas paroxetine was not different from placebo.

Conclusions

Inhibition of CYP3A4 by ketoconazole increases the exposure and some pharmacodynamic effects of oxycodone. Paroxetine pretreatment inhibits CYP2D6 without inducing relevant changes in oxycodone exposure, and partially blunts the pharmacodynamic effects of oxycodone due to intrinsic pharmacological activities. Pharmacodynamic changes associated with CYP3A4 inhibition may be clinically important in patients treated with oxycodone.

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Acknowledgements

This study was funded by the Division of Clinical Pharmacology & Toxicology, University Hospital Basel, Switzerland, and by Mundipharma Medical Company. We thank Natalie Grignaschi and Beatrice Vetter for the determination of oxycodone.

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Authors and Affiliations

  1. Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital, 4031, Basel, Switzerland

    Oliver Kummer, Felix Hammann, Claudine Moser, Jürgen Drewe & Stephan Krähenbühl

  2. Mundipharma Medical Company, Basel, Switzerland

    Olivier Schaller

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  1. Oliver Kummer
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  2. Felix Hammann
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  3. Claudine Moser
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  4. Olivier Schaller
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Corresponding author

Correspondence to Stephan Krähenbühl.

Additional information

Oliver Kummer and Felix Hammann contributed equally to this work.

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Kummer, O., Hammann, F., Moser, C. et al. Effect of the inhibition of CYP3A4 or CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone. Eur J Clin Pharmacol 67, 63–71 (2011). https://doi.org/10.1007/s00228-010-0893-3

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  • DOI: https://doi.org/10.1007/s00228-010-0893-3

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