Terbinafine hepatotoxicity

Fernandes NF, Geller SA, Fong TL. Terbinafine hepatotoxicity case report and review of the literature. Am J Gastroenterol 1998 93(3) 459-60. 

Anania FA, Rabin L. Terbinafine hepatotoxicity resulting in chronic biliary ductopenia and portal fibrosis. Am J Med 2002 112(9) 741-2. 

Iverson, S.L. and Uetrecht, J.P., Identification of a reactive metabolite of terbinafine Insights into terbinafine-induced hepatotoxicity, Chem. Res. Toxicol., 14, 175, 2001. 

Rare cases of hepatic failure, some leading to death or liver transplant, have occurred with the use of terbinafine for the treatment of onychomycosis in individuals with and without pre-existing liver disease. In the majority of liver cases reported in association with terbinafine use, the patients had serious underlying systemic conditions and an uncertain causal relationship with terbinafine. Terbinafine is not recommended for patients with chronic or active liver disease. Before prescribing terbinafine, assess pre-existing liver disease. Hepatotoxicity may occur in patients with and without preexisting liver disease. Pretreatment serum transaminase (ALT and AST) tests are advised for all patients before taking terbinafine. 

Because of the rare and unpredictable nature of hepatobihary reactions to terbinafine, the mechanism of hepatotoxicity has been hypothesized to be either immunological or metabolically mediated. A potentially toxic reactive metabolite of terbinafine, 7,7-dimethylhept-2-ene-4-jmal (TBF-A), the A-dealkylation product of terbinafine, has been identified in vitro (43). The authors speculated that this allylic aldehyde metabolite, formed by hver enzymes and conjugated with glutathione, would be transported across the canalicular membrane of hepatocytes and concentrated in the bile. The reactive monoglutathione conjugate could bind to hepatobiliary proteins and cause direct toxicity. Alternatively, it could modify canahcular proteins and lead to an immune-mediated reaction, causing cholestatic dysfunction. 

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