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The CYP2C8 inhibitor gemfibrozil does not affect the pharmacokinetics of zafirlukast

  • Pharmacokinetics and Disposition
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Abstract

Purpose

Gemfibrozil, a strong inhibitor of cytochrome P450 (CYP) 2C8 in vivo, was recently found to markedly increase the plasma concentrations of montelukast in humans. Like montelukast, zafirlukast is a substrate of CYP2C9 and CYP3A4 and a potent inhibitor of CYP2C8 in vitro. To investigate the contribution of CYP2C8 to the metabolism of zafirlukast in vivo, we studied the effect of gemfibrozil on the pharmacokinetics of zafirlukast.

Methods

Ten healthy subjects in a randomized cross-over study took gemfibrozil 600 mg or placebo twice daily for 5 days, and on day 3, a single oral dose of 20 mg zafirlukast. The plasma concentrations of zafirlukast were measured for 72 h postdose.

Results

The mean total area under the plasma concentration-time curve of zafirlukast during the gemfibrozil phase was 102% (geometric mean ratio; 95% confidence interval 89–116%) of that during the placebo phase. Furthermore, there were no statistically significant differences in the peak plasma concentration, time of peak concentration, or elimination half-life of zafirlukast between the phases.

Conclusions

Gemfibrozil has no effect on the pharmacokinetics of zafirlukast, indicating that CYP2C8 does not play a significant role in the elimination of zafirlukast.

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Acknowledgments

We would like to thank Mrs. Eija Mäkinen-Pulli, Mrs. Lisbet Partanen, and Mr. Jouko Laitila for skillful technical assistance. This study was supported by grants from the Helsinki University Central Hospital Research Fund, and the Sigrid Jusélius Foundation, Finland. None of the authors has any financial or personal relationships that could be perceived as influencing the research described. The experiments comply with the current laws of Finland, and the study protocol was approved by the Coordinating Ethics Committee of the Helsinki and Uusimaa Hospital District and by the Finnish Medicines Agency.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, P.O. Box 705, 00029 HUS, Helsinki, Finland

    Tiina Karonen, Pertti J. Neuvonen & Janne T. Backman

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  1. Tiina Karonen
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  2. Pertti J. Neuvonen
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  3. Janne T. Backman
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Correspondence to Janne T. Backman.

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Karonen, T., Neuvonen, P.J. & Backman, J.T. The CYP2C8 inhibitor gemfibrozil does not affect the pharmacokinetics of zafirlukast. Eur J Clin Pharmacol 67, 151–155 (2011). https://doi.org/10.1007/s00228-010-0908-0

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  • DOI: https://doi.org/10.1007/s00228-010-0908-0

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