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Effect of voriconazole and fluconazole on the pharmacokinetics of intravenous fentanyl

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

Abstract

Objective

Fentanyl is a widely used opioid analgesic, which is extensively metabolized by hepatic cytochrome P450 (CYP) 3A. Recent reports suggest that concomitant administration of CYP3A inhibitors with fentanyl may lead to dangerous drug interactions.

Methods

The potential interactions of fentanyl with triazole antifungal agents voriconazole and fluconazole were studied in a randomized crossover study in three phases. Twelve healthy volunteers were given 5 μg/kg of intravenous fentanyl without pretreatment (control), after oral voriconazole (400 mg twice on the first day and 200 mg twice on the second day), or after oral fluconazole (400 mg once on the first day and 200 mg once on the second day). Plasma concentrations of fentanyl, norfentanyl, voriconazole, and fluconazole were determined up to 24 h. Pharmacokinetic parameters were calculated using compartmental methods.

Results

The mean plasma clearance of intravenous fentanyl was decreased by 23% (range −22 to 48%; p < 0.05) and 16% (−34 to 53%; p < 0.05) after voriconazole and fluconazole administration, respectively. Voriconazole increased the area under the fentanyl plasma concentration-time curve by 1.4-fold (p < 0.05). The initial plasma concentrations and volume of distribution of fentanyl did not differ significantly between phases.

Conclusion

Both voriconazole and fluconazole delay the elimination of fentanyl significantly. Caution should be exercised, especially in patients who are given voriconazole or fluconazole during long-lasting fentanyl treatment, because insidiously elevated fentanyl concentration may lead to respiratory depression.

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Acknowledgements

We thank Mrs. Elina Kahra, Mrs. Eija Mäkinen-Pulli, and Kerttu Mårtensson for technical assistance and skilful determination of the voriconazole and fluconazole plasma concentrations. The study was supported by EVO grants no. 13821 and no. 13390 of the Hospital District of Southwest Finland, the Duocecim Foundation, Finland and the Sigrid Juselius Foundation, Finland. All experiments comply with the current laws in Finland, where the research was performed. There are no conflicts of interest.

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Authors and Affiliations

  1. Department of Anaesthesiology, Intensive Care, Emergency Care and Pain Medicine, University of Turku, P.O. Box 52, Kiinamyllynkatu 4–8, FI-20520, Turku, Finland

    Teijo I. Saari & Klaus T. Olkkola

  2. Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland

    Kari Laine

  3. Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland

    Mikko Neuvonen & Pertti J. Neuvonen

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  1. Teijo I. Saari
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  2. Kari Laine
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  5. Klaus T. Olkkola
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Correspondence to Teijo I. Saari.

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Saari, T.I., Laine, K., Neuvonen, M. et al. Effect of voriconazole and fluconazole on the pharmacokinetics of intravenous fentanyl. Eur J Clin Pharmacol 64, 25–30 (2008). https://doi.org/10.1007/s00228-007-0398-x

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  • DOI: https://doi.org/10.1007/s00228-007-0398-x

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