Molecular Modelling Analysis of the Metabolism of Paracetamol
Paracetamol is probably the most versatile and widely used analgesic and antipyretic drug all over the world and is also one of the commonest means of committing suicide. In humans, high doses of paracetamol can cause hepatotoxicity and sometimes nephrotoxicity. The drug is metabolized by different hepatic pathways to produce metabolites paracetamol sulfate, paracetamol glucuronide, NAPQI, PLCC and PNALCC. of these paracetamol sulfate and paracetamol glucuronide form the largest proportion. The metabolic activation of aspirin is associated with the formation of NAPQI which is highly toxic but is normally detoxified by reaction with glutathione. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) show that among paracetamol and its metabolites, NAPQI has the highest kinetic lability, lower solubility in water and possibly lower thermodynamic stability.
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