Itraconazole and other azole antifungal medications are essential in the treatment of deep mycoses, but the development of hepatotoxicity may limit their clinical utility. Anecdotally, glutathione precursors (e.g. S-adenosylmethionine) may ameliorate hepatotoxicity induced by itraconazole in dogs. The purpose of this study was to determine the effect of glutathione on itraconazole-induced cytotoxicity in an in vitro cell model. Canine hepatocytes in suspension (1.0 x 105 cells/ml) were treated with combinations of itraconazole (0, 2, 10, 50 μM) and reduced glutathione (0, 10, 100, 1000 μM). Cytotoxicity was determined at 0.5, 3, and 6 hours of incubation using a commercial lactate dehydrogenase assay, which measures leakage of intracellular enzyme from dead cells. Differences in % cytotoxicity were assessed by ANOVA. Without glutathione, % cytotoxicity increased over time at all concentrations of itraconazole (p = 0.0001 – 0.0060). Similarly, % cytotoxicity was increased at higher concentrations of itraconazole compared to lower concentrations at all time points (p = 0.0001 – 0.0078). At 6 hours, glutathione demonstrated a dose-dependent reduction in % cytotoxicity in cells treated with 2 μM itraconazole (p = 0.0333), but this effect was not seen at earlier time points (0.5 and 3 hours) or higher concentrations of the drug (10 and 50 μM). These findings suggest that glutathione may decrease low-dose, itraconazole-induced cytotoxicity in canine hepatocytes. Prospective clinical studies are needed to determine whether glutathione precursors are useful in the treatment or prevention of itraconazole-induced hepatotoxicity in dogs. Additionally, these results establish dose- and time-dependent cytotoxicity of itraconazole in canine hepatocytes in vitro, which may be a useful model for studying the pathogenesis of this adverse drug reaction.
Assistant Professor, Small Animal Internal Medicine
Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Illinois
Dr. Reinhart received her veterinary degree from the University of Illinois in 2010. Following a rotating internship at Cornell University, she completed her residency training in small animal internal medicine at Kansas State University and was board certified in 2014. Dr. Reinhart then moved to the University of Wisconsin where she entered a Ph.D. program in comparative biomedical sciences with a specific focus on sulfonamide hypersensitivity reactions and was granted the degree in 2017. While at UW, she also completed a residency in veterinary clinical pharmacology and served as a clinical instructor in small animal internal medicine. Dr. Reinhart recently joined the veterinary faculty at the University of Illinois as an Assistant Professor. Her current research interests include pharmacogenetics, drug metabolism, adverse drug reactions, and endocrinology.
Friday, June 15
10:30 AM – 10:45 AM
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