Influence of fluconazole on the pharmacokinetics of omeprazole in healthy volunteers

Kang, Byoung C.; Yang, Chang; Cho, Hae K.; Suh, Ok Kyung; Shin, Wonjae

doi:10.1002/bdd.291.abs

Cited by 11 publications

(14 citation statements)

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“…For example, pretreatment with voriconazole at 400 mg twice daily increased by 80% the mean steady-state AUC of phenytoin, a substrate for CYP2C9 and CYP2C19 (30). Fluconazole is another well-known potent inhibitor of CYP2C9 and CYP2C19 and a moderate inhibitor of CYP3A4 (4,17,23). Treatment with fluconazole (400 mg daily) for 6 days inhibited the CYP2C9-dependent hydroxylation of S-warfarin by 70% (4).…”

Section: Discussionmentioning

confidence: 99%

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

Hynninen

Olkkola

Leino

et al. 2006

Antimicrob Agents Chemother

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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,...

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Section: Discussionmentioning

confidence: 99%

“…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).…”

mentioning

confidence: 99%

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

Hynninen

Olkkola

Leino

et al. 2006

Antimicrob Agents Chemother

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“…Injections were 5 L. Retention times were 3.6, 4.6, and 5.6 minutes for EDDP, methadone, and the internal standard, respectively. Methadone and EDDP (d 0 ) were quantified by use of calibration curves (r 2 Ͼ 0.99 for both analytes) of peak area ratios, obtained by analysis of urine containing d 0 -methadone (4,8,12,20,40,60,100,200,300, and 500 ng/mL) and d 0 -EDDP (20, 40, 60, 100, 200, 300, 500, 1000, 1500, and 2000 ng/mL). Quality control samples contained 12, 60, and 300 ng/mL d 0methadone and 60, 300, and 1500 ng/mL d 0 -EDDP.…”

Section: Methodsmentioning

confidence: 99%

Role of hepatic and intestinal cytochrome P450 3A and 2B6 in the metabolism, disposition, and miotic effects of methadone

Kharasch

Hoffer

Whittington

et al. 2004

Clinical Pharmacology & Therapeutics

218

278

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First-pass intestinal metabolism is a determinant of methadone bioavailability. Intestinal and hepatic CYP3A activity only slightly affects human methadone N -demethylation but has no significant effect on methadone concentrations, clearance, or clinical effects. Greater rifampin effects, compared with troleandomycin and grapefruit juice, on methadone disposition suggest a major role for intestinal transporters and for other CYPs, such as CYP2B6. Interindividual variability and drug interactions affecting intestinal transporter and hepatic CYP3A and CYP2B6 activity may alter methadone disposition.

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“…Compared with a control group, the AUC of omeprazole has been observed to increase 6.3 times in those receiving fluconazole, possibly leading to an increased effect of omeprazole. 88 At steady state, omeprazole was shown to increase systemic exposure to voriconazole (C max and AUC increased by 15% and 41%, respectively), by an insignificant amount; therefore, no dose modification is necessary. 89 However, because of an increase in C max and AUC of omeprazole, it is recommended that for doses of omeprazole of 40 mg or more, the dose of the proton pump inhibitor be decreased by 50% when starting voriconazole.…”

Section: Chemotherapeutic Agentsmentioning

confidence: 99%

Management of Drug and Food Interactions with Azole Antifungal Agents in Transplant Recipients

2010

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Azole antifungal agents are frequently used in hematopoietic stem cell and solid organ transplant recipients for prevention or treatment of invasive fungal infections. However, because of metabolism by or substrate activity for various isoenzymes of the cytochrome P450 system and/or P-glycoprotein, azole antifungals have the potential to interact with many of the drugs commonly used in these patient populations. Thus, to identify drug interactions that may result between azole antifungals and other drugs, we conducted a literature search of the MEDLINE database (1966-December 2009) for English-language articles on drug interaction studies involving the azole antifungal agents fluconazole, itraconazole, voriconazole, and posaconazole. Another literature search between each of the azoles and the immunosuppressants cyclosporine, tacrolimus, and sirolimus, as well as the corticosteroids methylprednisolone, dexamethasone, prednisolone, and prednisone, was also conducted. Concomitant administration of azoles and immunosuppressive agents may cause clinically significant drug interactions resulting in extreme immunosuppression or toxicity. The magnitude and duration of an interaction between azoles and immunosuppressants are not class effects of the azoles, but differ between drug combinations and are subject to interpatient variability. Drug interactions in the transplant recipient receiving azole therapy may also occur with antibiotics, chemotherapeutic agents, and acid-suppressive therapies, among other drugs. Initiation of an azole antifungal in transplant recipients nearly ensures a drug-drug interaction, but often these drugs are required. Management of these interactions first involves knowledge of the potential drug interaction, appropriate dosage adjustments when necessary, and therapeutic or clinical monitoring at an appropriate point in therapy to assess the drug-drug interaction (e.g., immunosuppressive drug concentrations, signs and symptoms of toxicity). These aspects of drug interaction management are essential not only at the initiation of azole antifungal therapy, but also when these agents are removed from the regimen.

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Influence of fluconazole on the pharmacokinetics of omeprazole in healthy volunteers

Cited by 11 publications

References 0 publications

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

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

Role of hepatic and intestinal cytochrome P450 3A and 2B6 in the metabolism, disposition, and miotic effects of methadone

Management of Drug and Food Interactions with Azole Antifungal Agents in Transplant Recipients

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