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Antimicrob. Agents Chemother. doi:10.1128/AAC.00530-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Voriconazole increases while itraconazole decreases plasma meloxicam concentrations

Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland; Department of Anesthesiology, Intensive Care, Emergency Care and Pain Medicine, Turku University Hospital, Turku, Finland; Department of Laboratory Medicine, Division of Clinical Pharmacology at Karolinska Institute, Karolinska University Hospital, Huddinge, Stockholm, Sweden; Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; TYKSLAB, Unit of Clinical Pharmacology, Turku, Finland

^* To whom correspondence should be addressed. Email: vilhyn{at}utu.fi.

	Abstract

This study investigated the effect of voriconazole, an inhibitor of cytochrome P450 2C9 (CYP2C9) and CYP3A4, and itraconazole, an inhibitor of CYP3A4, on the pharmacokinetics and pharmacodynamics of meloxicam. Twelve healthy volunteers ingested in a cross-over study 15 mg meloxicam, without pretreatment (control), after voriconazole pretreatment, and after itraconazole pretreatment. Plasma concentrations of meloxicam, voriconazole, itraconazole and thromboxane B₂ (TxB₂) generation were followed. Compared to the control phase, voriconazole increased the mean area under the plasma concentration-time curve (AUC_0-72) of meloxicam by 47% (P < 0.001) and prolonged its mean half-life (t); by 51% (P < 0.01), without affecting its mean peak concentration (C_max). In contrast, itraconazole decreased the mean AUC_0-72 and C_max of meloxicam by 37% (P < 0.001) and by 64% (P < 0.001), respectively and prolonged its t and time to C_max. Plasma protein unbound fraction of meloxicam was unchanged by voriconazole and itraconazole. Lowered plasma meloxicam concentrations during the itraconazole phase were associated with decreased pharmacodymic effects of meloxicam, as observed by weaker inhibition of TxB₂ synthesis compared to the control and voriconazole phases. Voriconazole increases plasma concentrations of meloxicam, whereas itraconazole, unexpectedly, decreases plasma meloxicam concentrations, possibly by impairing its absorption.