Molecular Modelling Analysis of the Metabolism of Fenbufen
Fenbufen (FN) is an orally and parenterally effective NSAID, used in the treatment of rheumatoid arthritis and characterized by low water solubility, particularly at low pH. It is actually a pro-drug of [1,1’-biphenyl]-4-acetic acid (BPAA) formed in its metabolism. Like other NSAIDs it shows activity in humans as wells a wide variety of animals including mice, rats, guinea pigs and dogs. However, FN is also known to produce a high incidence of skin rash especially in women. In aerated solution FN was found to sensitize the formation of singlet oxygen indicating FN is a strong photodynamic agent. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that FN and its metabolites differ in their LUMO-HOMO energy differences indicating that they would differ in their kinetic ability. The molecular surface of the metabolite BPEN is found to abound most in electron-deficient regions so that BPEN is more likely to react with cellular antioxidant glutathione and nucleobases in DNA resulting in glutathione depletion and DNA damage respectively. Depletion of reduced form of glutathione will induce cellular toxicity by compromising the antioxidant status of the cell.
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