Fluconazole: A Potent Inhibitor of Cytochrome P-450-Dependent Drug-Metabolism in Mice and Humans in Vivo. Comparative Study with Ketoconazole.

Morita, Kunihiko; Konishi, Hiroki; Shimakawa, Harumi

doi:10.1248/cpb.40.1247

Cited by 33 publications

(17 citation statements)

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“…Eckhoff et al (20) also have reported a potent inhibitory effect of ketoconazole on steroidogenesis but only a weak effect of fluconazole (less than 50% inhibition at 10 24 M fluconazole) in a primary rat cell culture system. The fact that we registered a significant inhibitory effect of fluconazole at lower doses than previously described might be In fact, even a reversed order of inhibitory potencies on cytochrome P-450-dependent drug metabolism has been reported for ketoconazole and fluconazole in vivo (21). In addition, bioavailability of fluconazole is greater than of ketoconazole (7).…”

Section: Discussionsupporting

confidence: 52%

Long term control of hypercortisolism with fluconazole: case report and in vitro studies

Riedl

Maier²,

Zettinig³

et al. 2006

eur j endocrinol

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Objectives: To evaluate the efficacy of fluconazole as an alternative treatment for controlling hypercortisolism in Cushing's syndrome and to determine its effect on glucocorticoid production in vitro. Design: Case report and in vitro study in a University Clinic. Case: An 83 year old patient presented with recurrence of Cushing's syndrome due to pulmonary metastases three years after unilateral adrenalectomy. During a near fatal episode of sepsis she was started on fluconazole 200 mg/day intravenously which normalised cortisol excretion. The therapy was continued orally for 18 months. Upon temporary discontinuation and reintroduction of treatment, cortisol levels increased and normalized, respectively. At month 16, fluconazole had to be increased to a dose of 400 mg/day to keep cortisol excretion in the normal range. Disease progression was slow and no side effects occurred. In vitro results: Fluconazole in a concentration of 500 mM nearly abolished corticosterone production over 24 h from the adrenal adenoma cell line Y-1 (8.6^0.5% compared with control, P , 0.0001) and significantly reduced corticosterone production in concentrations of 50 mM (48.3^1.9% vs. control, P , 0.0001) and 5 mM (80.5^8.5% vs. control, P , 0.05).Conclusion: These results demonstrate for the first time that fluconazole normalises cortisol concentrations in vivo in a patient with Cushing's syndrome with adrenal carcinoma and inhibit glucocorticoid production in vitro in a cell line. Thus, fluconazole might be useful in controlling glucocorticoid excess in Cushing's syndrome and because of its lower toxicity might be preferable to ketoconazole.

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Section: Discussionsupporting

confidence: 52%

Long term control of hypercortisolism with fluconazole: case report and in vitro studies

Riedl

Maier²,

Zettinig³

et al. 2006

eur j endocrinol

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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%

“…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).…”

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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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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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“…These clinical findings suggest that the inhibitory action of fluconazole may not only be exerted on cytochrome P-450 in fungi, but that it may also affect hepatic microsomal cytochrome P-450 in the host. We have previously demonstrated that fluconazole inhibited cytochrome P-450-mediated drug metabolism in hepatic microsomes in vivo [9]. However, it is still not clear whether fluconazole is a nonselective inhibitor of various cytochrome P-450 isozymes in hepatic microsomes.…”

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confidence: 99%

Effect of fluconazole on theophylline disposition in humans

Konishi

Morita

Yamaji

1994

Eur J Clin Pharmacol

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The effect of fluconazole, an antimycotic that inhibits cytochrome P-450-mediated drug metabolism, on theophylline kinetics and the production of its metabolites were compared with those of enoxacin in 5 healthy subjects. All subjects received a single oral dose of 240 mg theophylline (aminophylline, 300 mg) after they had been given oral fluconazole 100 mg every 12 h or enoxacin 200 mg every 8 h for three consecutive days. Pretreatment with enoxacin decreased the total clearance (CLT) and elimination rate constant (Kel) of theophylline by 50% and 46%, respectively, without changing the volume of distribution (Vd), but there were no significant change in any pharmacokinetic parameter when fluconazole was administered. Enoxacin led to a 50% reduction in the metabolic clearance (CLM) of theophylline and to decreases of 69%, 59% and 38% in the formation clearance of the three theophylline metabolites, 3-methylxanthine (3-MX), 1-methyluric acid (1-MU), and 1,3-dimethyluric acid (1,3-DMU), respectively, accompanied by significant changes in the urinary recovery of theophylline and its metabolites. In contrast, treatment with fluconazole led only to a slight decrease in the CLM of theophylline (16%) and in the formation clearance of its metabolites (15%-18%), and there was no change in the renal clearance (CLR) of theophylline. The results indicate that fluconazole is a minor inhibitor of theophylline disposition compared with enoxacin, and they suggest that the inhibitory action of fluconazole is selective for certain cytochrome P-450 isozymes, but not for the cytochrome P-4501A involved in theophylline metabolism.

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Fluconazole: A Potent Inhibitor of Cytochrome P-450-Dependent Drug-Metabolism in Mice and Humans in Vivo. Comparative Study with Ketoconazole.

Cited by 33 publications

References 0 publications

Long term control of hypercortisolism with fluconazole: case report and in vitro studies

Long term control of hypercortisolism with fluconazole: case report and in vitro studies

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

Effect of fluconazole on theophylline disposition in humans

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