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The CYP2C8 inhibitor gemfibrozil does not increase the plasma concentrations of zopiclone

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

Abstract

Objective

Zopiclone is a short acting hypnotic, which is metabolised by cytochrome P450 (CYP) 3A4 and 2C8 in vitro. We studied the possible effect of gemfibrozil, an inhibitor of CYP2C8, on the pharmacokinetics and pharmacodynamics of zopiclone.

Methods

In a randomised 2-phase crossover study, 10 healthy volunteers took 600 mg gemfibrozil or placebo orally twice daily for 3 days. On day 3, each ingested a 7.5 mg dose of zopiclone. Plasma concentrations and urinary excretion of zopiclone and its two primary metabolites, plasma gemfibrozil, and psychomotor performance were measured. The effects of CYP2C8, CYP2C9 and CYP3A4 inhibitors on the depletion of zopiclone (500 nM) were studied in vitro in human liver microsomes.

Results

The pharmacokinetic variables of the parent zopiclone were not significantly affected by gemfibrozil. However, gemfibrozil raised the mean peak plasma concentration (Cmax) of N-oxide-zopiclone (1.6-fold; P<0.001) and that of N-desmethyl-zopiclone (1.2-fold; P<0.001). The mean area under the plasma concentration-time curve (\({\text{AUC}}_{{{\text{0}} - \infty }}\)) values of N-oxide-zopiclone and N-desmethyl-zopiclone were raised 2-fold (P<0.001) and 1.2-fold (P<0.01), respectively. The renal clearance of N-oxide-zopiclone was reduced by 48% by gemfibrozil (P<0.001). The pharmacodynamic effects of zopiclone, measured using psychometric tests, were not affected by gemfibrozil. In vitro, ketoconazole (1 μM) and itraconazole (8 μM) decreased the elimination rate of zopiclone enantiomers by about 65–95%, while montelukast (16 μM), gemfibrozil (200 μM) and sulfaphenazole (10 μM) had no appreciable effect.

Conclusions

Gemfibrozil does not increase the plasma concentrations of the parent zopiclone. Accordingly, CYP2C8 does not significantly metabolise zopiclone in vivo. However, as gemfibrozil raises the concentrations of two potentially active metabolites of zopiclone, slightly enhanced effects of zopiclone by gemfibrozil can not be excluded.

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Acknowledgements

This study was supported by grants from the Helsinki University Central Hospital Research Fund, the National Technology Agency, 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 Ethics Committee for Studies in Healthy Subjects and Primary Care of the Hospital District of Helsinki and Uusimaa, and the Finnish National Agency for Medicines.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

    Aleksi Tornio, Pertti J. Neuvonen & Janne T. Backman

  2. Department of Clinical Pharmacology, University of Helsinki, Haartmaninkatu 4, 00290, Helsinki, Finland

    Janne T. Backman

Authors
  1. Aleksi Tornio
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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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Tornio, A., Neuvonen, P.J. & Backman, J.T. The CYP2C8 inhibitor gemfibrozil does not increase the plasma concentrations of zopiclone. Eur J Clin Pharmacol 62, 645–651 (2006). https://doi.org/10.1007/s00228-006-0155-6

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  • DOI: https://doi.org/10.1007/s00228-006-0155-6

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