15- Metabolism of mefenamic acid – a molecular modelling analysis

Fazlul Huq

Discipline of Biomedical Science, School of Medical Sciences, Faculty of Medicine, The University of Sydney, Australia. Telephone: +61 2 9351 9522  Fax: +61 2 9351 9520 E-mail : F.Huq@usyd.edu.au.

Abstract

Mefenamic acid is a NSAID that is widely used in analgesia, has been implicated in several cases of nephrotoxicity including acute renal failure and tubulointestinal nephritis. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that MFA and its metabolites have similar LUMO-HOMO energy differences except MFA-Glu which has a much smaller value. The molecular surface of most reactive metabolite MFA-Glu is found to possess some electron-deficient (blue) regions so that it can react readily with cellular nucleophiles such as glutathione and nucleobases in DNA. Reaction with glutathione would induce cellular toxicity associated with oxidative stress whereas the oxidation of nucleobases would cause DNA damage. However, because MFA-Glu, being a terminal metabolite, is expected to be easily excreted so that the consequences of such adverse reactions may be decreased.

Key words: Mefenamic acid, NSAID, analgesic, toxicity, molecular modelling

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