EVALUATION OF FLUCONAZOLE-INDUCED CARDIOTOXICITY IN MICE: FUNCTIONAL AND STRUCTURAL ANALYSIS

Fluconazole is an antifungal widely used in clinical practice. It is known for its ability to inhibit the biosynthesis of ergosterol, a key component of fungal cell membranes, leading to fungal death or inhibition of their growth. Its use has been associated with cardiac alterations, such as QT interval prolongation, and in some cases Torsades de pointes. Considering this, we aimed to evaluate the cardiotoxicity of fluconazole. Male Swiss Webster mice (8 weeks old) were divided into two groups: the control group (CTR), which received the vehicle (1% dimethyl sulfoxide in water), and the fluconazole group (FLU), which received 125 mg/kg of the drug. Both treatments were administered orally by daily gavage during 28 days. All animals were monitored by the electrocardiogram one day before treatment, on the fifteenth day, and one day after the last dose. We also evaluated the incidence of arrythmia following a stress protocol using caffeine and dobutamine, and subsequently quantified the infarct area using 1% 2,3,5-triphenyltetrazolium chloride (TTC). Besides this, organ morphometry and histology were investigated. In the electrocardiogram analysis, wave durations and intervals were evaluated, and no differences were observed between the CTR and FLU groups. During the stress protocol, a higher incidence of proarrhythmic events was observed in the FLU group (71.5%); however, this difference was not statistically significant from CTR, possibly due to the sample size. No differences were detected in infarct area measurements between the groups. In the morphometric analysis, we evaluated the weights of the heart, atria, kidneys, liver, and spleen, normalized by tibial length. The only significant difference was observed in liver weight, which increased after exposure to FLU. Histological analysis showed no significant changes in the heart. Overall, FLU at the dose tested did not appear to affect cardiac parameters; however, further investigation into arrhythmia susceptibility and potential liver toxicity is needed.

This work was supported by São Paulo Research Foundation (FAPESP): Project #s 21/15122-0, 21/05584-7, 2023/14219-6​