Molecular Modelling Analysis of the Metabolism of Ceftiofur
Ceftiofur sodium (CF) is a third generation broad-spectrum cephalosphorin, that is active against both Gram-positive and Gram-negative pathogenic bacteria of veterinary importance and has been approved for subcutaneous treatment of certain respiratory diseases in cattle, horses, pigs, poultry and dogs. CF is rapidly metabolized to its active metabolite desfuroylceftiofur (DFC) and furoic acid (FA) after parenteral administration. DFC is further metabolized to disulfides such as desfuroylceftiofur dimer (DFC-D), desfuroylceftiofur cysteine disulfide (DFC-CYS) and desfuroylceftiofur glutathione (DFC-GS) and desfuroylcetiofur protein conjugate that may be playing a role in the activity and efficacy of CF. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that metabolite DFC-D has the lowest LUMO-HOMO energy difference so that it would be most reactive kinetically. CF and DFC are also expected to be significantly more labile than FA and DFC-CYS. The higher kinetic lability and the presence of electron-deficient regions on the molecular surfaces of DFC-D, CF and DFC mean that the compounds would react more readily with reduced form of glutathione and nucleobases in DNA. The depletion of glutathione level will induce cellular toxicity resulting from oxidative stress and oxidation of nucleobases in DNA will cause DNA damage. In actual fact, the effects of such adverse reactions may be lower in the case of most reactive metabolite DFC-D because of its much greater ease in excretion.
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