Lamisil (terbinafine) is widely prescribed and effective antifungal drug that causes idiosyncratic liver toxicity.  Terbinafine undergoes extensive metabolism including N-dealkylation to yield 6,6-dimethyl-2-hepten-4-ynal (TBF-A).  This reactive allylic aldehyde was proposed to transiently form a glutathione conjugate that enables off target damage of the bile duct leading to liver toxicity.  Nevertheless, TBF-A toxicological relevance remains unclear due to a lack of identification of pathways leading to and competing with TBF-A formation.  We propose terbinafine undergoes rapid N-demethylation to form desmethyl-terbinafine (dTBF) followed by subsequent N-dealkylation to yield TBF-A and naphthylmethylamine (NMA).  This pathway is the most probable one based on modeling terbinafine N-dealkylation using deep learning neural networks.  We are experimentally testing the hypothesis and model using <i>in vitro</i> reactions with human liver microsomes.  Based on LC-MS analysis, we identified primary and secondary metabolites corresponding to N-dealkylated and hydroxylated products of terbinafine.  Aldehyde metabolites from N-dealkylation were not observed directly, and they were trapped with dansylhydrazine labeling.  Our identification of dTBF and its hydroxylated derivatives from terbinafine reactions suggest a rapid initial N-demethylation.  Furthermore, we identified NMA and oxidized derivatives from dTBF reactions.  These compounds are co-metabolites of TBF-A, allowing us to infer its formation even though we were not able to directly identify it directly or trap it with glutathione.  Together, these data support the proposed two-step pathway for TBF-A formation from terbinafine under biological conditions.  On-going kinetic studies will reveal the efficiency of subsequent TBF-A formation and competing detoxification pathways.  Moreover, inhibitor phenotyping revealed CYP1A2 and 2C9 oxidize terbinafine and CYP1A2, 2B6, 2C9, and 3A4 oxidize dTBF in pathways competing with TBF-A formation.  Overall, we have identified terbinafine metabolic pathways including preferred bioactivation pathways for TBF-A and competing oxidation pathways.  Knowledge of these mechanistic details will confirm the most probable model prediction for TBF-A formation and experimentally demonstrate whether the efficiency of the pathway could contribute to reported liver toxicity.<br/>

Terbinafine bioactivation pathways to liver toxicity assessed using predictive modeling and experimental approaches

254th National Meeting (2017)

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