Sl. Iverson et Jp. Uetrecht, Identification of a reactive metabolite of terbinafine: Insights into terbinafine-induced hepatotoxicity, CHEM RES T, 14(2), 2001, pp. 175-181
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.