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Antimicrobial Agents and Chemotherapy, June 2006, p. 1967-1972, Vol. 50, No. 6
0066-4804/06/$08.00+0     doi:10.1128/AAC.01483-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Effects of the Antifungals Voriconazole and Fluconazole on the Pharmacokinetics of S-(+)- and R-(–)-Ibuprofen

Department of Anesthesiology and Intensive Care, Turku University Hospital, Turku, Finland,¹ Department of Pharmacology and Clinical Pharmacology, University of Turku, Turku University Hospital, Turku, Finland,² Department of Medical Laboratory Sciences and Technology, Division of Clinical Pharmacology at Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden,³ Department of Clinical Pharmacology, University of Helsinki, and Helsinki University Central Hospital, Helsinki, Finland⁴

Received 17 November 2005/ Returned for modification 29 January 2006/ Accepted 17 March 2006

Our objective was to study the effects of the antifungals voriconazole and fluconazole on the pharmacokinetics of S-(+)- and R-(–)-ibuprofen. Twelve healthy male volunteers took a single oral dose of 400 mg racemic ibuprofen in a randomized order either alone, after ingestion of voriconazole at 400 mg twice daily on the first day and 200 mg twice daily on the second day, or after ingestion of fluconazole at 400 mg on the first day and 200 mg on the second day. Ibuprofen was ingested 1 h after administration of the last dose of voriconazole or fluconazole. Plasma concentrations of S-(+)- and R-(–)-ibuprofen were measured for up to 24 h. In the voriconazole phase, the mean area under the plasma concentration-time curve (AUC) of S-(+)-ibuprofen was 205% (P < 0.001) of the respective control value and the mean peak plasma concentration (C_max) was 122% (P < 0.01) of the respective control value. The mean elimination half-life (t_1/2) was prolonged from 2.4 to 3.2 h (P < 0.01) by voriconazole. In the fluconazole phase, the mean AUC of S-(+)-ibuprofen was 183% of the control value (P < 0.001) and its mean C_max was 116% of the control value (P < 0.05). The mean t_1/2 of S-(+)-ibuprofen was prolonged from 2.4 to 3.1 h (P < 0.05) by fluconazole. The geometric mean S-(+)-ibuprofen AUC ratios in the voriconazole and fluconazole phases were 2.01 (90% confidence interval [CI], 1.80 to 2.22) and 1.82 (90% CI, 1.72 to 1.91), respectively, i.e., above the bioequivalence acceptance upper limit of 1.25. Voriconazole and fluconazole had only weak effects on the pharmacokinetics of R-(–)-ibuprofen. In conclusion, voriconazole and fluconazole increased the levels of exposure to S-(+)-ibuprofen 2- and 1.8-fold, respectively. This was likely caused by inhibition of the cytochrome P450 2C9-mediated metabolism of S-(+)-ibuprofen. A reduction of the ibuprofen dosage should be considered when ibuprofen is coadministered with voriconazole or fluconazole, especially when the initial ibuprofen dose is high.

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