7. Molecular modelling analysis of the metabolism of diclofenac

Fazlul Huq and Ali Alshehri

School of Biomedical Sciences, Faculty of Health Sciences, The University of Sydney

Abstract:

Diclofenac (DF) is a non-steroidal anti-inflammatory drug (NSAID) that is frequently prescribed in treating osteoarthritis, rheumatoid arthritis and ankylosing spondylitis and as an analgesic. However, the use of the drug has been associated with occasional hepatic toxicity. The pharmacological efficacy of DF is believed to be associated with inhibition of the arachidonic acid cascade at the level cyclooxygenaes-2 (COX-2). DF undergoes extensive phase I and phase II metabolisms involving aromatic hydroxylations and conjugations with glucose. In humans and rats, the principal metabolites of DF are 4’-hydroxydiclofenac (4’HDF), 5-hydroxydiclofenac (5HDF) and the reactive metabolite diclofenac-1-O-acyl glucuronide (DF1AG). Although the exact mechanism of DF induced hepatotoxicity remains unclear, it is believed to be associated at least in part to one or more of its metabolites especially 4’- and 5-hydroxy derivatives, their quinoneimine intermediates and its acyl glucuronide. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations using the program Spartan ’02 show that DF and its metabolites differ in solvation energy, surface charge distribution, dipole moment, thermodynamic stability and kinetic lability. OFQIDF and TFQIDF but not DF1AG appear to be most labile kinetically and also their surfaces abound most in electron-deficient regions. The high kinetic lability and the presence of electron-deficient regions allow the metabolites to react readily with glutathione and nucleobases in DNA, thus causing cellular toxicity and damage to DNA. The surface of DF1AG is found to be most negatively charged so that it will be most subject to electrophilic attack. It is possible that the binding of DF1AG with cellular proteins is mediated by electrical interaction.

Key words: Diclofenac, anti-inflammatory drug, COX, hepatotoxicity, glucuronidation, molecular modelling

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