Identification of novel glutathione conjugates of terbinafine in liver microsomes and hepatocytes across species

Abstract1. Terbinafine (TBF), a common antifungal agent, has been associated with rare incidences of hepatotoxicity. It is hypothesized that bioactivation of TBF to reactive intermediates and subsequent binding to critical cellular proteins may contribute to this toxicity. In the present study, we have characterized the bioactivation pathways of TBF extensively in human, mouse, monkey, dog and rat liver microsomes and hepatocytes.2. A total of twenty glutathione conjugates of TBF were identified in hepatocytes; thirteen of these conjugates were also detected in liver microsomes. To the best of our knowledge only two of these conjugates have been reported previously. The conjugates were categorized into three groups based on their mechanism of formation: a) alkene/alkyne oxidation followed by glutathione conjugation, with or without N-demethylation, b) arene oxidation followed by glutathione conjugation, with or without N-demethylation, and c) N-dealkylation followed by glutathione conjugation of the allyl...