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

Raschi, Emanuel; Poluzzi, Elisabetta; Koci, Ariola; Caraceni, Paolo; Ponti, Fabrizio De

doi:10.4254/wjh.v6.i8.601

Cited by 62 publications

(67 citation statements)

References 56 publications

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“…Canalicular BS secretion is one of the major driving forces of bile flow and inhibition of BSEP is a well-characterized mechanism of acquired cholestasis (Stieger, 2010), with the number of drugs inhibiting BSEP constantly growing (Dawson et al, 2012). An analysis of the Food and Drug Administration Adverse Event Reporting System database (http://www.fda.gov/ Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/ AdverseDrugEffects/) revealed that antimycotics are involved in approximately 3% of all DILI cases (Raschi et al, 2014). Moreover, antifungal azoles have been associated with elevated levels of serum liver enzymes as well as liver injury occasionally leading to liver failure (Hann et al, 1993;Gearhart, 1994;Adriaenssens et al, 2001;Chang et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Role of Multidrug Resistance Protein 3 in Antifungal-Induced Cholestasis

et al. 2016

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Drug-induced liver injury is an important clinical entity resulting in a considerable number of hospitalizations. While drug-induced cholestasis due to the inhibition of the bile salt export pump (BSEP) is well investigated, only limited information on the interaction of drugs with multidrug resistance protein 3 (MDR3) exists and its role in the pathogenesis of drug-induced cholestasis is poorly understood. Therefore, we aimed to study the interaction of drugs with MDR3 and the effect of drugs on canalicular lipid secretion in a newly established polarized cell line system that serves as a model of canalicular lipid secretion. LLC-PK 1 cells were stably transfected with human Na 1 -taurocholate cotransporting polypeptide, BSEP, MDR3, and ABCG5/G8 and grown in the Transwell system. Apical phospholipid secretion and taurocholate transport were assayed to investigate the effect of selected drugs on MDR3-mediated phospholipid secretion as well as inhibition of BSEP. The established cell line displayed vectorial bile salt transport and specific phosphatidylcholine secretion into the apical compartment. The antifungal azoles, posaconazole, itraconazole, and ketoconazole, significantly inhibited MDR3-mediated phosphatidylcholine secretion. In contrast, amoxicillin clavulanate and troglitazone did not interfere with MDR3 activity. Drugs interfering with MDR3 activity did not display a parallel inhibition of BSEP. Our in vitro model for MDR3-mediated phospholipid secretion facilitates parallel screening for MDR3 and BSEP inhibitors. Our data demonstrate that the cholestatic potential of certain drugs may be aggravated by simultaneous inhibition of BSEP and MDR3.

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Section: Discussionmentioning

confidence: 99%

Role of Multidrug Resistance Protein 3 in Antifungal-Induced Cholestasis

et al. 2016

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“…Different drugs have been convincingly documented to cause liver injury in numerous case reports and case series[10]. Paracetamol has been consistently reported as a leading cause of acute liver failure, whereas chlorpromazine, halothane, sulpiride and amoxicillin-clavulanate such as found to be the most common drugs leading to hepatotoxicity in all prospective studies[11].…”

Section: Suspecting and Diagnosing Dili: A Current Dilemmamentioning

confidence: 99%

Drug-induced liver injury: Towards early prediction and risk stratification

Raschi

Ponti

2017

WJH

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Drug-induced liver injury (DILI) is a hot topic for clinicians, academia, drug companies and regulators, as shown by the steadily increasing number of publications and agents listed as causing liver damage (http://livertox.nih.gov/). As it was the case in the past decade with drug-induced QT prolongation/arrhythmia, there is an urgent unmet clinical need to develop tools for risk assessment and stratification in clinical practice and, in parallel, to improve prediction of pre-clinical models to support regulatory steps and facilitate early detection of liver-specific adverse drug events. Although drug discontinuation and therapy reconciliation still remain the mainstay in patient management to minimize occurrence of DILI, especially acute liver failure events, different multidisciplinary attempts have been proposed in 2016 to predict and assess drug-related risk in individual patients; these promising, albeit preliminary, results strongly support the need to pursue this innovative pathway.

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“…5–7 Few studies have examined the relative and absolute risks of acute liver injury associated with use of oral azole antifungals in clinical practice, and none have evaluated laboratory tests of liver inflammation or function. Moreover, it remains unclear whether chronic liver disease increases the risk of azole-associated acute liver injury.…”

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confidence: 99%

Oral Azole Antifungal Medications and Risk of Acute Liver Injury, Overall and by Chronic Liver Disease Status

Carbonari

Lewis

et al. 2016

The American Journal of Medicine

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BACKGROUND Reports on associations between azole antifungal medications and acute liver injury are inconsistent and have not been based on liver-related laboratory tests. We evaluated incidence rates of acute liver injury associated with oral azole antifungals. METHODS We conducted a cohort study among Kaiser Permanente Northern California members who initiated an oral azole antifungal in an outpatient setting during 2004–2010. We determined development of: (1) liver aminotransferases >200 U/L, (2) severe acute liver injury (coagulopathy with hyperbilirubinemia), and (3) acute liver failure. We calculated incidence rates of endpoints. Cox regression was used to determine whether chronic liver disease was a risk factor for outcomes. RESULTS Among 195,334 azole initiators (178,879 fluconazole; 14,296 ketoconazole; 1653 itraconazole; 478 voriconazole; 28 posaconazole), incidence rates (events/1000 person-years [95% confidence intervals (CIs)]) of liver aminotransferases >200 U/L were similarly low with fluconazole (13.0 [11.4–14.6]), ketoconazole (19.3 [13.8–26.3]), and itraconazole (24.5 [10.6–48.2]). Rates were higher with voriconazole (181.9 [112.6–278.0]) and posaconazole (191.1 [23.1–690.4]), but comparable. Severe acute liver injury was uncommon with fluconazole (2.0 [1.4–2.7]), ketoconazole (2.9 [1.1–6.3]), and itraconazole (0.0 [0.0–11.2]), but more frequent with voriconazole (16.7 [2.0–60.2]) and posaconazole (93.4 [2.4–520.6]). One patient developed acute liver failure due to ketoconazole. Pre-existing chronic liver disease increased risks of aminotransferases >200 U/L (hazard ratio 4.68 [95% CI, 3.68–5.94]) and severe acute liver injury (hazard ratio 5.62 [95% CI, 2.56–12.35]). CONCLUSIONS Rates of acute liver injury were similarly low for fluconazole, ketoconazole, and itraconazole. Events were more common among voriconazole and posaconazole users but were comparable. Preexisting chronic liver disease increased risk of azole-induced liver injury.

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

Cited by 62 publications

References 56 publications

Role of Multidrug Resistance Protein 3 in Antifungal-Induced Cholestasis

Role of Multidrug Resistance Protein 3 in Antifungal-Induced Cholestasis

Drug-induced liver injury: Towards early prediction and risk stratification

Oral Azole Antifungal Medications and Risk of Acute Liver Injury, Overall and by Chronic Liver Disease Status

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