Molecular Modelling Analysis of the Metabolism of Terbinafine
Terbinafine (TBN) is an orally active allylamine derivative that has fungicidal activity against dermatocytes and many pathogenic fungi. The drug is extensively metabolized in humans with systemic clearance being dependent primarily on its biotransformation. The five most prominent metabolites found in plasma are N-desmethylterbinafine (DTBN), hydroxyterbinafine (HTBN), N-desmethylhydroxy- terbinafine (DHTBN), carboxyterbinafine (CTBN) and N-desmethylcarboxyterbinafine (DCTBN) that together account for 25% of the total urinary excretion. Four other metabolites are 1-naphthaldehyde (NAL), 1-naphthalenemethanol (NM), 1-naphthanoic acid (NA) and N-desmethylterbinafine aldehyde (DATBN). Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that TBN and its metabolites have LUMO-HOMO energy differences ranging from 4.22 to 4.73 eV based on from DFT calculations. The values suggest neither TBN nor any of its metabolites would be highly reactive or extremely inert. The molecular surface of TBN and the metabolites DATBN, NAL and DTBN are found to have significant electron-deficient regions so that they may be subject to nucleophilic attack by glutathione and nucleobases in DNA. DATBN that has been implicated as a possible cause for toxicity of TBN is found to abound most in electron-deficient regions although it has a slightly higher LUMO-HOMO energy difference than NAL. Reaction with glutathione would cause glutathione depletion resulting into oxidative stress and therefore cellular toxicity whereas the oxidation of nucleobases in DNA would cause DNA damage.
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