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Systemic uptake of miconazole during vaginal suppository use and effect on CYP1A2 and CYP3A4 associated enzyme activities in women

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Abstract

Purpose

To investigate if the ordinary use of a vaginal suppository containing miconazole results in systemic absorption that is sufficient to affect the activities of CYP1A2 and CYP3A4, which are major drug- and steroid-metabolising enzymes.

Methods

In 20 healthy non-pregnant women aged 18–45 years, the serum concentration of miconazole was determined following the use of a vaginal suppository containing 1,200 mg miconazole. Enzyme activities of CYP1A2 and CYP3A4 were determined as metabolic ratios of caffeine (CMR = (AFMU + 1MU + 1MX)/17DMU) and quinidine (QMR = 3-hydroxy-quinidine/quinidine) respectively before and 34 h after insertion of the suppository. Miconazole was analysed by LC-MS/MS, while caffeine and metabolites were analysed by HPLC-UV and quinidine and hydroxy-quinidine were analysed by HPLC fluorescence.

Results

All 20 women had measurable concentrations of miconazole in serum (mean ± SD: 12.9 ± 5.6 μg/L; range: 3.5–24.6 μg/L). Although not statistically significant, an association between the serum concentrations of miconazole and the inhibition of CYP1A2 activity was indicated. No relation was observed between the CYP3A4 activity and the miconazole serum concentration.

Conclusions

Miconazole is absorbed via the vaginal mucosa to the systemic circulation in measurable concentrations. Our data indicate a concentration-dependent inhibition of CYP1A2, but the effect is negligible compared with the variation in the activity of CYP1A2 and is regarded to be of no clinical significance to the women. However, further studies on the ability of miconazole to be transferred across the placenta or to interfere with the placental function are warranted to secure safe use during pregnancy.

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Acknowledgements

This work was supported by Clinical Pharmacology and the Department of Environmental Medicine at the University of Southern Denmark and with grants from Hartmann Fonden (number A1461), Beckett Fonden (number 80530), and Kong Christian den tiendes Fond (number 75/2008).

We are indebted to Vibeke Kvist Pedersen and Stine Rosendahl for excellent technical assistance.

Conflict of interest

The authors declare that there are no conflicts of interest.

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Authors and Affiliations

  1. Department of Environmental Medicine, Institute of Public Health, University of Southern Denmark, JB Winsløwsvej 17, 5000, Odense C, Denmark

    Mia Birkhøj Kjærstad, Flemming Nielsen & Helle Raun Andersen

  2. Clinical Pharmacology, Institute of Public Health, University of Southern Denmark, JB Winsløwsvej 19, 5000, Odense C, Denmark

    Flemming Nielsen, Lene Nøhr-Jensen, Stine Zwisler & Kim Brøsen

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  1. Mia Birkhøj Kjærstad
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  2. Flemming Nielsen
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Correspondence to Mia Birkhøj Kjærstad.

Additional information

Clinical trial registry: www.clinicaltrials.gov

Registration number: NCT00668538

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Kjærstad, M.B., Nielsen, F., Nøhr-Jensen, L. et al. Systemic uptake of miconazole during vaginal suppository use and effect on CYP1A2 and CYP3A4 associated enzyme activities in women. Eur J Clin Pharmacol 66, 1189–1197 (2010). https://doi.org/10.1007/s00228-010-0906-2

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  • DOI: https://doi.org/10.1007/s00228-010-0906-2

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