4- Metabolism of ketoprofen – a molecular modelling analysis

 Fazlul Huq

Discipline of Biomedical Science, Faculty of Medicine, The University of Sydney

 Address reprint requests and correspondences to:

Dr. Fazlul Huq, Discipline of Biomedical Science,

Faculty of Medicine, C42, The University of Sydney,

PO Box 170 East Street Lidcombe NSW 1825, Australia.

Phone: 061 2 9351 9522; Fax: 061 2 9351 9520

Email: F.Huq@usyd.edu.au

Abstract

Ketoprofen (KP) is a non-steroidal anti-inflammatory drug (NSAID) that is widely used in humans and veterinary medicine in the treatment of acute and chronic rheumatoid arthritis and various painful conditions. Increasing evidence suggests that reactive oxygen species (ROS) may contribute significantly to the development if intestinal lesions due to KP as are true with many other NSAIDs. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that molecular surfaces of KP and its metabolites abound in neutral green and have electron-rich red and yellow regions so that they may be subject to lyophilic and electrophilic attacks. The molecular surfaces of KP and its metabolites are also found to possess some electron-deficient blue regions so that the compounds may be subject to nucleophilic attacks such as those due to glutathione and nucleobases in DNA resulting into glutathione depletion and oxidation of nucleobases. The depletion of glutathione produces oxidative stress as it compromises the antioxidant status of the cell whereas oxidation of nucleobases causes DNA damage. The oxidative stress in turn may cause lipid peroxidation and damage to other biomolecules including proteins, enzymes and also DNA.

 Key words: Ketoprofen, NSAID, veterinary medicine, toxicity, glutathione, molecular modelling

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