Journal of Pharmacology and Toxicology1816-496x2152-100xAcademic Journals Inc.10.3923/jpt.2006.354.361HuqFazlul 4200614Naltrexone (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.]]>Bertolotti, M., A. Ferrari, G. Vitale, M. Stefani and T. Trenti et al.,199727505511Chatterjie, N. and C.E. Inturrisi,197518490492Davidson, D., R. Swift and E. Fritz,199620732739Davidson, D., T. Palfai and R. Swift,199923195203Lee, Y.K., S.W. Park, Y.K. Kim, D.J. Kim, J. Jeong, H. Myrick and Y.H. Kim,200540297301Misra, A.L., R. Bloch, J. Vardy, S.J. Mule and K. Verebely,19764276280Meyer, M.C., A.B. Starughn, M.W. Lo and C.C. Whitney,1984451519Pillali, O., M.O. Hamad, P.A. Crooks and A.L. Stinchcomb,2004in vitro human skin diffusion and concurrent biotransformation of 3-O-Alkyl Carbonate Prodrugs of Naltrexone.]]>2111461152Ramenskaya, G.V., E.V. Shikh, A.P. Arzamastsev and V.G. Kukes,20053913Takemori, A.E. and P.S. Portghese,199232239269Veebey, K. and S.J. Mule,19752357363Volpicelli, J.R., A.I. Alterman and M. Hayashida,199249876880