Comparative Hepatotoxicity of Fluconazole, Ketoconazole, Itraconazole, Terbinafine, and Griseofulvin in Rats

Abstract

Oral ketoconazole was recently the subject of regulatory safety warnings because of its association with increased risk of inducing hepatic injury. However, the relative hepatotoxicity of antifungal agents has not been clearly established. The aim of this study was to compare the hepatotoxicity induced by five commonly prescribed oral antifungal agents. Rats were treated with therapeutic oral doses of griseofulvin, fluconazole, itraconazole, ketoconazole, and terbinafine. After 14 days, only ketoconazole had significantly higher ALT levels (p = 0.0017) and AST levels (p = 0.0008) than the control group. After 28 days, ALT levels were highest in the rats treated with ketoconazole followed by itraconazole, fluconazole, griseofulvin, and terbinafine, respectively. The AST levels were highest in the rats treated with ketoconazole followed by itraconazole, fluconazole, terbinafine, and griseofulvin, respectively. All drugs significantly elevated ALP levels after 14 days and 28 days of treatment (p < 0.0001). The liver enzyme levels suggested that ketoconazole had the highest risk in causing liver injury followed by itraconazole, fluconazole, terbinafine, and griseofulvin. However, histopathological changes revealed that fluconazole was the most hepatotoxic, followed by ketoconazole, itraconazole, terbinafine, and griseofulvin, respectively. Given the poor correlation between liver enzymes and the extent of liver injury, it is important to confirm liver injury through histological examination.

Therapeutic effect of an anti-human-TNF-alpha antibody and itraconazole on feline infectious peritonitis

“…Azole antifungal agents, including ICZ, are known to have hepatotoxicity as a side effect and possibly to induce cholestasis and jaundice [29][30][31][32]. As increases in liver enzymes are observed in cats with FIP, the development of adverse effects after ICZ administration was of concern.…”

Acute generalized exanthematous pustulosis due to terbinafine

“…Terbinafine is an attractive medication because of its once‐daily dosing and has minimal drug–drug interactions (Ibrahimi, Gunawardane, Sepehr, & Reynolds, ). Although terbinafine has been reported to induce hepatic injury, it is associated with a lower risk of clinically significant transaminitis than other antifungal agents (Khoza, Moyo, & Ncube, ). Cutaneous adverse effects occur in 1–3% of patients on terbinafine, and the incidence of serious side effects, including AGEP, subacute cutaneous lupus erythematosus, and erythema multiforme, is only 0.04% (Eyler et al, ).…”

Spectrophotometric study of ketoconazole binding with citrate capped silver nanoparticles and its monitoring in human plasma samples

“…Therefore, beside antifungal potential, it is one of the few available remedies for Cushing's syndrome . Although this drug is effective in decreasing cortisol and reducing the clinical effects of Cushing's syndrome, it is life‐threatening due to the risk of severe hepatotoxicity …”

“…7 Although this drug is effective in decreasing cortisol and reducing the clinical effects of Cushing's syndrome, it is life-threatening due to the risk of severe hepatotoxicity. 8 Moreover, it has been reported that this antifungal agent is able to induce a variety of heart function side effects, such as long-QT syndrome 9 and ventricular arrhythmias. 10 Although, clear mechanism of this action is not obvious, it is in center of sanctifies attention.…”