Identification of a reactive metabolite of terbinafine: Insights into terbinafine-induced hepatotoxicity

Oral terbinafine treatment for superficial fungal infections of toe and fin gernails is associated with a low incidence (1:45000) of hepatobiliary dysf unction. Due to the rare and unpredictable nature of this adverse drug reac tion, the mechanism of toxicity has been hypothesized to be either an uncom mon immunological or metabolically mediated effect. However, there is littl e evidence to support either mechanism, and toxic metabolites of terbinafin e have not been identified. We incubated terbinafine with both rat and huma n liver microsomal protein in the presence of GSH and were able to trap an allylic aldehyde, 7,7-dimethylhept-2-ene-4-ynal (TBFA), which corresponds t o the N-dealkylation product of terbinafine. TBF-A was also prepared synthe tically and reacted with excess GSH to yield conjugates with HPLC retention times and mass spectra identical to those generated in the microsomal incu bations. The major GSH conjugate, characterized by H-1 NMR, corresponds to addition of GSH in a 1,6-Michael fashion. There remains a second electrophi lic site on this metabolite, which can bind either to a second molecule of GSH or to cellular proteins via a 1,4-Michael addition mechanism. Moreover, we demonstrated that the formation of the GSH conjugates was reversible. W e speculate that this allylic aldehyde metabolite, formed by liver enzymes and conjugated with GSH, would be transported across the canalicular membra ne of hepatocytes and concentrated in the bile. The mono-GSH conjugate, whi ch is still reactive, could bind to hepatobiliary proteins and lead to dire ct toxicity. Alternatively, it could modify canalicular proteins and lead t o an immune-mediated reaction causing cholestatic dysfunction.