Inhibition of 11β-hydroxysteroid dehydrogenase 2 by the fungicides itraconazole and posaconazole

Beck, Katharina R.; Bächler, M.; Vuorinen, Anna; Wagner, Sandra; Akram, Muhammad; Griesser, Ulrich J.; Temml, Veronika; Klusoňová, Petra; Yamaguchi, Hideaki; Schuster, Daniela; Odermatt, Alex

doi:10.1016/j.bcp.2017.01.010

Cited by 50 publications

(31 citation statements)

References 89 publications

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“…It is thus not surprising that differing affinity between these enzymes would be suggested in clinical observations. In fact, recent in vitro work confirmed the relative specificity of the type 2 isoform to both posaconazole and itraconazole (5). In this report, the 50% inhibitory (IC 50 ) level of posaconazole was found to be 460 Ϯ 98 nM for 11␤-HSD2 (a value exceeded by patient serum posaconazole concentrations) with little in vitro effect on 11␤-HSD1 activity.…”

supporting

confidence: 48%

In Vivo 11β-Hydroxysteroid Dehydrogenase Inhibition in Posaconazole-Induced Hypertension and Hypokalemia

Thompson

Chang

Wittenberg

et al. 2017

Antimicrob Agents Chemother

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We describe a case of apparent mineralocorticoid excess (AME) secondary to posaconazole therapy and suggest the biochemical mechanism. Clinical and laboratory investigation confirmed 11␤-hydroxysteroid dehydrogenase inhibition and withholding therapy led to a resolution of all clinical and laboratory abnormalities. Posaconazole was later restarted at a lower dose and prevented recurrence of this syndrome. Additional studies are necessary to determine the frequency of posaconazole-induced AME and whether other azole antifungals can be associated with this phenomenon.KEYWORDS antifungal, posaconazole, side effects P osaconazole is a triazole antifungal agent with a broad spectrum of antifungal activity. Frequently used for the prevention of fungal infections in high-risk populations, this agent is also useful during the treatment of multiple forms of aspergillosis (1). Recent studies have shown that the new posaconazole delayed-release tablets have superior bioavailability compared to the liquid suspension formulation (2, 3). As higher serum posaconazole concentrations have been associated with improved clinical responses (4), this formulation has been a welcome addition to available treatment options. However, higher serum and tissue levels are likely to reveal previously undescribed toxicity as adverse events attributed to "off-target" effects are observed.We present here a 67-year-old man with chronic cavitary aspergillosis of the left lung and no history of hypertension. At the time of initial evaluation he was afebrile with a blood pressure of 114/66 mm Hg. The patient had previously received voriconazole (more than 1 year earlier) with the complaint of visual hallucinations. He had also previously received isavuconazole with frequent serum blood levels noted Ͼ10 g/ml despite standard dosing. He refused to take either medication again and had been off antifungal therapy for 6 weeks prior to the initial evaluation. His intake laboratory values, including basic chemistries and liver tests, were within normal limits (potassium 4.1 mmol/liter). Posaconazole tablets were started (300 mg twice daily on day 1, followed by 300 mg daily). The patient tolerated the medication without complaint; however, on his return visit 35 days later, his blood pressure was noted to be 165/89 mm Hg. All other vital signs were within normal limits. A review of his laboratory values (Quest Diagnostics) revealed a potassium level of 3.4 mmol/liter and a serum posaconazole level of 4.36 g/ml. Additional work-up was initiated and found complete suppression of renin and aldosterone, with increased 11-deoxycortisol and estradiol levels

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supporting

confidence: 48%

In Vivo 11β-Hydroxysteroid Dehydrogenase Inhibition in Posaconazole-Induced Hypertension and Hypokalemia

Thompson

Chang

Wittenberg

et al. 2017

Antimicrob Agents Chemother

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“…This hypothesised mechanism for the effect of posaconazole was first signalled by recent studies (6). These set out to identify potential 11βHSD inhibitors among approved drugs: several azole antifungals were identified as active.…”

Section: Discussionmentioning

confidence: 82%

Mineralocorticoid hypertension and hypokalaemia induced by posaconazole

Boughton

Taylor

Ghataore

et al. 2018

Endocrinology, Diabetes &Amp; Metabolism Case Reports

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SummaryWe describe severe hypokalaemia and hypertension due to a mineralocorticoid effect in a patient with myelodysplastic syndrome taking posaconazole as antifungal prophylaxis. Two distinct mechanisms due to posaconazole are identified: inhibition of 11β hydroxylase leading to the accumulation of the mineralocorticoid hormone 11-deoxycorticosterone (DOC) and secondly, inhibition of 11β hydroxysteroid dehydrogenase type 2 (11βHSD2), as demonstrated by an elevated serum cortisol-to-cortisone ratio. The effects were ameliorated by spironolactone. We also suggest that posaconazole may cause cortisol insufficiency. Patients taking posaconazole should therefore be monitored for hypokalaemia, hypertension and symptoms of hypocortisolaemia, at the onset of treatment and on a monthly basis. Treatment with mineralocorticoid antagonists (spironolactone or eplerenone), supplementation of glucocorticoids (e.g. hydrocortisone) or dose reduction or cessation of posaconazole should all be considered as management strategies.Learning points:Combined hypertension and hypokalaemia are suggestive of mineralocorticoid excess; further investigation is appropriate.If serum aldosterone is suppressed, then further investigation to assess for an alternative mineralocorticoid is appropriate, potentially using urine steroid profiling and/or serum steroid panelling.Posaconazole can cause both hypokalaemia and hypertension, and we propose that this is due to two mechanisms – both 11β hydroxylase inhibition and 11β HSD2 inhibition.Posaconazole treatment may lead to cortisol insufficiency, which may require treatment; however, in this clinical case, the effect was mild.First-line treatment of this presentation would likely be use of a mineralocorticoid antagonist.Patients taking posaconazole should be monitored for hypertension and hypokalaemia on initiation and monthly thereafter.

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“…In addition, negative inotropic effects have been observed following the intravenous administration of itraconazole. There are also both in vitro and clinical data suggesting that itraconazole and posaconazole may inhibit 11␤-hydroxysteroid dehydrogenase type 2 (11␤-HSD2) and 11␤-hydroxylase (11␤OH), resulting in the triad of hypertension, hypokalemia, and alkalosis due to cortisol inactivation (29)(30)(31). In some cases, this effect has been shown to be potentially dose related, at least for posaconazole (30).…”

Section: Discussionmentioning

confidence: 99%

Effects of Food and Omeprazole on a Novel Formulation of Super Bioavailability Itraconazole in Healthy Subjects

Lindsay

Mudge

Thompson

2018

Antimicrob Agents Chemother

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To address the limited bioavailability and intolerance of the conventional itraconazole (ITZ) formulations, a new formulation labeled super bioavailability (SUBA) itraconazole has been developed; however, the specific effects of food and gastric pH are unknown. This study evaluated the pharmacokinetic profile of SUBA itraconazole under fasting and fed conditions, as well as with the concomitant administration of a proton pump inhibitor. First, the effect of food was assessed in an open-label, randomized, crossover bioavailability study of 65-mg SUBA itraconazole capsules (2 65-mg capsules twice a day) in healthy adults (n = 20) under fasting and fed conditions to steady-state levels. Second, an open-label, two-treatment, fixed-sequence comparative bioavailability study in healthy adults (n = 28) under fasted conditions compared the pharmacokinetics of a single oral dose of SUBA itraconazole capsules (2 65-mg capsules/day) with and without coadministration of daily omeprazole delayed-release capsules (1 40-mg capsule/day) under steady-state conditions. In the fed and fasted states, SUBA itraconazole demonstrated similar concentrations at the end of the dosing interval, with modestly lower total and peak ITZ exposure being shown when it was administered under fed conditions than when it was administered in the fasted state, with fed state/fasted state ratios of 78.09% (90% confidence interval [CI], 74.49 to 81.86%) for the area under the concentration-time curve over the dosing interval (14,183.2 versus 18,479.8 ng · h/ml), 73.05% (90% CI, 69.01 to 77.33%) for the maximum concentration at steady state (1,519.1 versus 2,085.2 ng/ml), and 91.53% (90% CI, 86.41 to 96.96%) for the trough concentration (1,071.5 versus 1,218.5 ng/ml) being found. When dosed concomitantly with omeprazole, there was a 22% increase in the total plasma exposure of ITZ, as measured by the area under the concentration-time curve from time zero to infinity (P = 0.0069), and a 31% increase in the peak plasma exposure of ITZ, as measured by the maximum concentration (P = 0.0083).

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Inhibition of 11β-hydroxysteroid dehydrogenase 2 by the fungicides itraconazole and posaconazole

Cited by 50 publications

References 89 publications

In Vivo 11β-Hydroxysteroid Dehydrogenase Inhibition in Posaconazole-Induced Hypertension and Hypokalemia

In Vivo 11β-Hydroxysteroid Dehydrogenase Inhibition in Posaconazole-Induced Hypertension and Hypokalemia

Mineralocorticoid hypertension and hypokalaemia induced by posaconazole

Effects of Food and Omeprazole on a Novel Formulation of Super Bioavailability Itraconazole in Healthy Subjects

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