A cohort study on the risk of acute liver injury among users of ketoconazole and other antifungal drugs

Rodríguez, García; Duque,; Castellsague,; Pérez-Gutthann,; Stricker,

doi:10.1046/j.1365-2125.1999.00095.x

Cited by 131 publications

(78 citation statements)

References 30 publications

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“…In this study, main selection criteria regards the role code assigned to the drug (i.e., only "Primary Suspect", "Secondary Suspect" or "Interacting", whereas cases where antimycotics were reported as "Concomitant" were not included) and information on age and gender (records with missing of mild, asymptomatic, reversible elevations in serum transaminases has been estimated to be 5%-10% [29] . Also García Rodríguez et al [30] found that ketoconazole was associated with significant risk. Very recently, a systematic review and meta-analysis documented an overall incidence of 3.6%-4.2%, which may be considered as common [31] .…”

Section: Data Selection and Analysismentioning

confidence: 99%

Assessing liver injury associated with antimycotics: Concise literature review and clues from data mining of the FAERS database

Raschi¹,

Poluzzi²,

Koci³

et al. 2014

WJH

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AIM: To inform clinicians on the level of hepatotoxic risk among antimycotics in the post-marketing setting, following the marketing suspension of oral ketoconazole for drug-induced liver injury (DILI). METHODS:The publicly available international FAERS database (2004)(2005)(2006)(2007)(2008)(2009)(2010)(2011) was used to extract DILI cases (including acute liver failure events), where antimycotics with systemic use or potential systemic absorption were reported as suspect or interacting agents. The reporting pattern was analyzed by calculating the reporting odds ratio and corresponding 95%CI, a measure of disproportionality, with time-trend analysis where appropriate. RESULTS:From 1687284 reports submitted over the 8-year period, 68115 regarded liver injury. Of these, 2.9% are related to antimycotics (1964 cases, of which 112 of acute liver failure). Eleven systemic antimycotics (including ketoconazole and the newer triazole derivatives voriconazole and posaconazole) and terbinafine (used systemically to treat onychomicosis) generated a significant disproportionality, indicating a post-marketing signal of risk. CONCLUSION:Virtually all antimycotics with systemic action or absorption are commonly reported in clinically significant cases of DILI. Clinicians must be aware of this aspect and monitor patients in case switch is considered, especially in critical poly-treated patients under chronic treatment.

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Section: Data Selection and Analysismentioning

confidence: 99%

Assessing liver injury associated with antimycotics: Concise literature review and clues from data mining of the FAERS database

Raschi¹,

Poluzzi²,

Koci³

et al. 2014

WJH

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“…The most common reported adverse events were stomach pain, diarrhea, and rash [50-53]. Itraconazole is reported to cause acute liver injury at an incidence rate of 10.4 per 100,000 [54]. Therefore, it is recommended to obtain baseline ALT and AST before initiating treatment [55].…”

Section: Itraconazolementioning

confidence: 99%

Treatment of Tinea Capitis

Alkeswani

Cantrell²,

Elewski

2019

Skin Appendage Disord

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Tinea capitis is a common fungal infection of the hair of the scalp affecting predominately prepubertal children. In the US, griseofulvin has been considered a first-line therapy agent for tinea capitis since the 1960s. However, it has been falling out of favor due to significant treatment failure, high cost, and long duration of treatment. Other antifungal agents have been researched as an alternative to griseofulvin. This paper will review the relevant pharmacologic properties, dosing, cost, efficacy, and adverse events profile for griseofulvin, terbinafine, itraconazole, fluconazole, and some adjuvant therapy options such as selenium sulfide shampoos and topical ketoconazole.

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“…Our results suggest that the activation of PXR by clotrimazole is less effective on the transcriptional activation of MRP3 in HepG2 cells. We therefore focused on the hepatotoxicity of azole antifungal agents (García Rodríguez et al, 1999;Kuroda et al, 2004;Girois et al, 2005), because it has been reported that Mrp3 expression is significantly increased in cholestasis-induced liver injury (Wagner et al, 2003). To confirm the cytotoxicity of clotrimazole, LDH activity was measured in HepG2 cells treated with clotrimazole or rifampicin.…”

Section: Novel Transactivation Of the Mrp3 Genementioning

confidence: 99%

Activation of p38 Mitogen-Activated Protein Kinase by Clotrimazole Induces Multidrug Resistance-Associated Protein 3 Activation through a Novel Transcriptional Element

Sasaki

Inami

Numata

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Multidrug resistance-associated protein 3 (MRP3) is a basolaterally localized transporter in the liver and contributes to the transport of various metabolites such as conjugates of endogenous compounds and drugs from hepatocytes. MRP3 expression in the human liver is low under normal physiologic conditions but is induced by drug treatment. Although several studies have identified a region necessary for the basal transcription of MRP3, no region that responds to drugs has been reported. To identify the xenobiotic-responsive elements of MRP3, we constructed a luciferase reporter plasmid containing the MRP3 59-flanking region up to 210 kb upstream from the transcription start site. Among typical nuclear receptor ligands, clotrimazole dramatically enhanced MRP3 reporter activity in HepG2 cells, whereas rifampicin had no effect. We then conducted MRP3 reporter assays with deletion or mutation constructs to identify a clotrimazole-responsive element. The element was located approximately 26.8 kb upstream from the MRP3 transcription start site. Overexpression of the pregnane X receptor did not enhance clotrimazole-mediated transcription. We found that clotrimazole was toxic to HepG2 cells and we therefore investigated whether mitogen-activated protein kinase (MAPK) activation is involved in the transactivation of MRP3 by clotrimazole. p38 MAPK inhibitor SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole] suppressed MRP3 mRNA expression induced by clotrimazole, whereas c-Jun N-terminal kinase inhibitor SP600125 (1,9-pyrazoloanthrone) and extracellular signal-regulated kinase inhibitor PD98059 [2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one] did not. Phosphorylated p38 MAPK was detected in HepG2 cells treated with clotrimazole. These results suggest that activation of the p38 MAPK pathway induces the transcriptional activation of MRP3.

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A cohort study on the risk of acute liver injury among users of ketoconazole and other antifungal drugs

Abstract: Ketoconazole and itraconazole were the two oral antifungal associated with a marked increase of clinical acute liver injury. The risk associated with ketoconazole should be taken into account when prescribing it as initial treatment for uncomplicated fungal infections.

Cited by 131 publications

References 30 publications

Assessing liver injury associated with antimycotics: Concise literature review and clues from data mining of the FAERS database

Assessing liver injury associated with antimycotics: Concise literature review and clues from data mining of the FAERS database

Treatment of Tinea Capitis

Activation of p38 Mitogen-Activated Protein Kinase by Clotrimazole Induces Multidrug Resistance-Associated Protein 3 Activation through a Novel Transcriptional Element

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