Hepatotoxicity of Antimycotics Used for Invasive Fungal Infections: In Vitro Results.

Sandra Doß,Heike Potschka,Martin Sauer,Steffen Mitzner,Fanny Doß

doi:10.1155/2017/9658018

Abstract

Purpose. Drug-induced liver injury (DILI) is the most common cause of liver injury and a serious clinical problem; antimycotics are involved in approximately 3% of all DILI cases. The hepatotoxicity of many drugs, including the antimycotics, is poorly screened in human models. Methods. In a standardized assay the cytotoxicity on hepatocytes of different concentrations (Cmax, 5x Cmax, and 10x Cmax) of the antimycotics used for systemic infections was tested. Anidulafungin (ANI), liposomal amphotericerin B (L-AmB), caspofungin (CASPO), fluconazole (FLUCO), and voriconazole (VORI) were incubated with HepG2/C3A cells. After incubation, the viability of cells (XTT test, LDH release, trypan blue staining), the synthesis of albumin, the cytochrome 1A2 activity, and the cell death (DNA fragmentation) were determined. Kruskal-Wallis and Mann–Whitney tests were used for statistical analyses. Results. L-AmB, ANI, and CASPO showed a mild hepatotoxicity in the Cmax concentrations. Higher concentrations of anidulafungin led to a severe impairment of hepatocyte viability and function. The azoles FLUCO and VORI had a higher hepatotoxic potential in all concentrations. Conclusion. Antimycotics, especially azoles, used for systemic infections should be given with caution in patient with liver insufficiency or liver failure or high risk for this; therefore, therapeutic drug monitoring should be used. Further studies with this approach are encouraged.

Highlights

Drug-induced liver injury (DILI) is often responsible for hepatic dysfunction, the termination of drug development, or postmarket withdrawal of approved drugs [1,2,3]
The cell count was significantly decreased in the Cmax concentrations of fluconazole (FLUCO) and voriconazole (VORI) compared with the negative control in medium and plasma (Figure 1(a))
A further significant decrease in higher concentrations was only seen after incubation with anidulafungin (ANI) down to zero cells in the 10x Cmax concentration

Summary

Introduction

Drug-induced liver injury (DILI) is often responsible for hepatic dysfunction, the termination of drug development, or postmarket withdrawal of approved drugs [1,2,3]. DILI is a rare but serious clinical problem that is associated with significant morbidity and mortality. It is generally categorized as “idiosyncratic” or “intrinsic.” These two forms of DILI are contrasted in their manifestation and diagnosis. Acetaminophen (APAP) is a common example for intrinsic hepatotoxins [4]; an APAP overdosage is the most frequent cause of drug-induced acute liver failure. It is dose-dependent and is reproducible in animal models [2]. Idiosyncratic DILI is typically rare and less reproducible It occurs, when individuals are exposed to environmental or metabolic predispositions [5, 6]

Methods

Results

Conclusion