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Journal of Pharmacology and Toxicology

Year: 2006  |  Volume: 1  |  Issue: 4  |  Page No.: 328 - 336

Molecular Modelling Analysis of the Metabolism of Zaleplon

Fazlul Huq

Abstract

Zaleplon (ZAL) is a sleep inducing agent with a prompt onset of action. It is rapidly metabolized with 88% of the dose appearing in the urine (71%) and faces (17%) as metabolites. A number of products including M1, M2 and DDZAL are produced from ZAL. M2 is the major metabolite in man whereas DZAL and DDZAL are the major plasma metabolites in rat, mouse and dog. Both M1 and M2 can form glucuronides. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that among ZAL and its metabolites, DDZAL has the smallest LUMO-HOMO energy difference so that it would be most kinetically labile. The high kinetic lability and the presence of electron-deficient regions on the molecular surface would make DDZAL the most toxic metabolite as it would react readily with glutathione and nucleobases in DNA. Reaction with glutathione would cause glutathione depletion thus inducing oxidative stress whereas that with nucleobases in DNA would cauase DNA damage.

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