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Journal of Pharmacology and Toxicology

Year: 2006  |  Volume: 1  |  Issue: 5  |  Page No.: 407 - 417

Molecular Modelling Analysis of the Metabolism of Codeine

Fazlul Huq and J. Al-Shuneigat

Abstract

Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that the metabolite codeinone is more kinetically labile than the parent drug codeine and other metabolites and that it can be subject to nucleophilic attack due to the presence of electron-deficient regions on its molecular surface. This means that the metabolite can react with glutathione thus causing glutathione depletion and can also cause oxidation of nucleobases in DNA thus producing DNA damage. Depletion of glutathione induces oxidative stress as it compromises the anti-oxidant status of the cell.

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