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Journal of Pharmacology and Toxicology

Year: 2006  |  Volume: 1  |  Issue: 4  |  Page No.: 354 - 361

Molecular Modelling Analysis of the Metabolism of Naltrexone

Fazlul Huq


Naltrexone (NTX) is a potent opioid antagonist that has been used in the treatment of alcohol dependence and opioid addiction. In humans, it has a plasma half-life of 2-14 h and volume distribution of 15 L kg-1. NTX therapy is associated with a number of gastrointestinal adverse effects including abdominal pain, nausea and vomiting, thus limiting its clinical utility. A major disappointment has been the poor patience compliance with the therapy. Reasons for non-adherence include poor motivation, cognitive impairment and the adverse effects of the drug. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that NTX, NTXOL and HMNTXOL have high LUMO-HOMO energy differences so that they would be kinetically inert. The presence of electron-deficient regions on the molecular surface indicates that the compounds can react with cellular glutathione, thus causing glutathione depletion and hence oxidative stress. Comparable surface area and volume for NTX and NTXOL indicates that the two compounds can be substrates for the same binding sites in opioid receptors.

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