ArticleBiochemical pharmacology2018
Lamisil (terbinafine) toxicity: Determining pathways to bioactivation through computational and experimental approaches.
Article in Biochemical pharmacology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
10 citing papers in PubMed, 16 citations in OpenAlex.
- An update on the global treatment of invasive fungal infections.Future microbiology · 2023Review
- A Critical Review on the Dosing and Safety of Antifungals Used in Exotic Avian and Reptile Species.Journal of fungi (Basel, Switzerland) · 2023Review
- The potential applications of artificial intelligence in drug discovery and development.Physiological research · 2021Review
- Impacts of diphenylamine NSAID halogenation on bioactivation risks.Toxicology · 2021Article
- Significance of Multiple Bioactivation Pathways for Meclofenamate as Revealed through Modeling and Reaction Kinetics.Drug metabolism and disposition: the biological fate of chemicals · 2021Article
- XenoNet: Inference and Likelihood of Intermediate Metabolite Formation.Journal of chemical information and modeling · 2020Article
- Comprehensive kinetic and modeling analyses revealed CYP2C9 and 3A4 determine terbinafine metabolic clearance and bioactivation.Biochemical pharmacology · 2019Article
- The application of artificial neural networks in metabolomics: a historical perspective.Metabolomics : Official journal of the Metabolomic Society · 2019Review
- CYP2C19 and 3A4 Dominate Metabolic Clearance and Bioactivation of Terbinafine Based on Computational and Experimental Approaches.Chemical research in toxicology · 2019Article
- Examining the Potential of Developing and Implementing Use of Adiponectin-Targeted Therapeutics for Metabolic and Cardiovascular Diseases.Frontiers in endocrinology · 2019Review
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
Lamisil (terbinafine) may cause idiosyncratic liver toxicity through a proposed toxicological mechanism involving the reactive metabolite 6,6-dimethyl-2-hepten-4-ynal (TBF-A). TBF-A toxicological relevance remains unclear due to a lack of identification of pathways leading to and competing with TBF-A formation. We resolved this knowledge gap by combining computational modeling and experimental kinetics of in vitro hepatic N-dealkylation of terbinafine. A deep learning model of N-dealkylation predicted a high probability for N-demethylation to yield desmethyl-terbinafine followed by N-dealkylation to TBF-A and marginal contributions from other possible pathways. We carried out steady-state kinetic experiments with pooled human liver microsomes that relied on development of labeling methods to expand metabolite characterization. Those efforts revealed high levels of TBF-A formation and first order decay during metabolic reactions; actual TBF-A levels would then reflect the balance between those processes as well as reflect the impact of stabilizing adduction with glutathione and other biological molecules. Modeling predictions and experimental studies agreed on the significance of N-demethylation and insignificance of N-denaphthylation in terbinafine metabolism, yet differed on importance of direct TBF-A formation. Under steady-state conditions, the direct pathway was the most important source of the reactive metabolite with a V
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