title: Effects of the antifungals voriconazole and fluconazole on the pharmacokinetics of s-(+)- and R-(-)-Ibuprofen.
abstract: 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.
authors.affiliation: Department of Anesthesiology and Intensive Care, Turku University Hospital, Finland. vilhyn@utu.fi
authors.forename: Ville-Veikko
authors.initials: VV
authors.lastname: Hynninen
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Olkkola
authors.forename: Kari
authors.initials: K
authors.lastname: Leino
authors.forename: Stefan
authors.initials: S
authors.lastname: Lundgren
authors.forename: Pertti J
authors.initials: PJ
authors.lastname: Neuvonen
authors.forename: Anders
authors.initials: A
authors.lastname: Rane
authors.forename: Mika
authors.initials: M
authors.lastname: Valtonen
authors.forename: Hanna
authors.initials: H
authors.lastname: Vyyryläinen
authors.forename: Kari
authors.initials: K
authors.lastname: Laine
mesh_terms: D000328:Adult; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000935:Antifungal Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D015725:Fluconazole / Q000493:pharmacokinetics / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D007052:Ibuprofen / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D013810:Therapeutic Equivalency; D014230:Triazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D065819:Voriconazole
chemical_list: D018712:Analgesics, Non-Narcotic; D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; D015725:Fluconazole; D065819:Voriconazole; D007052:Ibuprofen