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. Voriconazole is a novel triazole antifungal agent, available as oral and intravenous formulations, with potent activity against a broad spectrum of clinically significant pathogens, including Aspergillus, Cryptococcus, and Candida species (5,8,27). Voriconazole is metabolized by the cytochrome P450 (CYP) enzyme system, mainly by the polymorphic enzyme CYP2C19 and to a lesser extent by the polymorphic enzymes CYP2C9 and CYP3A4 (13; G. Mikus, M. Drzevinska, V. Schoevel, J. Burhenne, K. D. Riedel, T. Thomsen, M. M. Hoffmann, J. Weis, J. Rengelshausen, and W. E. Haefeli, Abstr. 7th Congr. Eur. Assoc. Clin. Pharmacol. Ther., abstr. 418, 2005). In vivo studies have shown that addition of voriconazole at 300 mg twice daily to a 30-mg oral dose of warfarin in healthy volunteers resulted in a doubling of the prothrombin time from 8.4 to 16.6 s (28), probably due to inhibition of CYP2C9. In addition, coadministration of voriconazole has significantly increased the area under the plasma concentration-time curve (AUC) of phenytoin, a substrate of CYP2C9 (30); the AUC of omeprazole, a substrate of CYP2C19 (http://www.emea.eu .int./humandocs/Humans/EPAR/vfend/vfend.htm); and the AUC of cyclosporine, which is metabolized by CYP3A4 (31).Fluconazole is another azole antifungal agent and a welldocumented potent inhibitor of CYP2C9-catalyzed reactions both in vitro (3,20) and in vivo (4, 18) and a weaker inhibitor of CYP3A4-catalyzed reactions (23). It has also been found to inhibit CYP2C19-catalyzed reactions both in vitro (34) and in vivo (17). However, there are few data on the possible interactions between fluconazole and nonsteroidal anti-inflammatory drugs (NSAIDs). Treatment with fluconazole significantly increased the AUC of the CYP2C9 substrate celecoxib (7), and recently, it has been shown that coadministration of fluconazole and a novel cyclooxygenase 2 (COX-2)-selective inhibitor,...

Confirmation That Cytochrome P450 2C8 (CYP2C8) Plays a Minor Role in (S)-(+)- and (R)-(-)-Ibuprofen Hydroxylation in Vitro

“…In the same study, the effect on the AUC of the IBU (S)-(ϩ)-enantiomer was not statistically significant. Conversely, fluconazole (CYP2C9 inhibitor) increases (S)-(ϩ)-IBU AUC up to 1.9-fold, while having no effect on the AUC of (R)-(Ϫ)-IBU (Hynninen et al, 2006). On the basis of such data, one could argue that CYP2C8 and CYP2C9 play a significant role in the clearance of (R)-(Ϫ)-IBU and (S)-(ϩ)-IBU, respectively.…”

“…Such a range encompasses the clinically relevant free (ϳ1 M) and total (ϳ100 M) plasma concentrations of each enantiomer (Davies, 1998;Andersson et al, 2004;Takanohashi et al, 2007). Integration of the above in vitro data, with known human ADME information, may help rationalize reports describing IBU PK-P450 inhibitor combinations and IBU PK-P450 genotype associations (Kirchheiner et al, 2002;Garcia-Martin et al, 2004;Martinez et al, 2005;Hynninen et al, 2006;Bell et al, 2007;Tornio et al, 2007).…”

“…Such data have led various groups to conclude that both CYP2C forms catalyze the oxidative metabolism of IBU, and attempts have been made to evaluate the impact of both CYP2C9 and CYP2C8 genotype on the PK, pharmacodynamics, and side-effect profile of IBU enantiomers (Kirchheiner et al, 2002;Garcia-Martin et al, 2004; Martinez et al, 2005;Pilotto et al, 2007;Blanco et al, 2008). Clinical drug interaction studies with known inhibitors of CYP2C9 (e.g., fluconazole) and CYP2C8 (e.g., gemfibrozil) have been conducted also (Hynninen et al, 2006;Tornio et al, 2007).…”

“…Therefore, additional studies were warranted, given the number of reports describing IBU PK-P450 inhibitor combinations and IBU PK-P450 genotype associations (Kirchheiner et al, 2002;Garcia-Martin et al, 2004;Martinez et al, 2005;Hynninen et al, 2006;Bell et al, 2007;Tornio et al, 2007). To this end, an LC-MS/MS assay was developed to monitor the formation of both 2-OH and 3-OH in vitro.…”

“…Such data have led various groups to conclude that both CYP2C forms catalyze the oxidative metabolism of IBU, and attempts have been made to evaluate the impact of both CYP2C9 and CYP2C8 genotype on the PK, pharmacodynamics, and side-effect profile of IBU enantiomers (Kirchheiner et al, 2002;Garcia-Martin et al, 2004; Martinez et al, 2005;Pilotto et al, 2007;Blanco et al, 2008). Clinical drug interaction studies with known inhibitors of CYP2C9 (e.g., fluconazole) and CYP2C8 (e.g., gemfibrozil) have been conducted also (Hynninen et al, 2006;Tornio et al, 2007).However, it is worth noting that CYP2C8-selective chemical inhib- ABBREVIATIONS: ADME, absorption-distribution-metabolism-excretion; IBU, 2-(4-isobutylphenyl)propionic acid, ibuprofen; P450, cytochrome P450; rCYP2C8, recombinant cytochrome P450 2C8; rCYP2C9, recombinant cytochrome P450 2C9; PK, pharmacokinetics; mAb, monoclonal antibody; HLM, human liver microsomes; 2-OH, 2-hydroxyibuprofen; 3-carboxy-IBU, 3-(4-(1-carboxyethyl)phenyl)-2-methylpropanoic acid, 3-carboxyibuprofen; 3-OH, 2-(4-(3-hydroxy-2-methylpropyl)phenyl)-propanoic acid, 3-hydroxyibuprofen; HPLC, high-performance liquid chromatography; NR, normalized rate; TNR, total normalized rate; LC-MS/MS, liquid chromatography-tandem mass spectrometry; CL int , intrinsic clearance (V max /K m ); OATP, organic anion-transporting peptide; AUC, area under the plasma concentration versus time curve. …”