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1- Molecular modelling analysis of the metabolism of
Nefazodone
Fazlul Huq
Discipline of
Biomedical Science, Faculty of Medicine, The University of Sydney
Address reprint requests and correspondences to:Dr. Fazlul Huq,
Discipline of Biomedical Science, Faculty of Medicine, C42, The
University of Sydney,
PO Box 170, Lidcombe, NSW 1825, Australia.,
Telephone: +61 2 9351 9522 Fax: +61 2 9351 9520E-mail
:
F.Huq@usyd.edu.au
Abstract
Nefazodone (NEF) is a novel antidepressant that shows no cardiac
toxicity or anticholinergic activity common with tricyclic
antidepressants. However, there are several reported cases of
idiosyncratic adverse reactions of the drug including hepatobiliary
dysfunction and cholestasis. It has been suggested that the
metabolites p-ONE-NEF, p-ONE-mCPP and p-ONE-TRZ may be playing a
significant role in NEF-induced hepatitic necrosis. The compounds can
react with reduced form of glutathione resulting into its depletion,
thus causing cellular toxicity. Molecular modelling analyses based on
molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G*
level) calculations show that p-ONE-NEF, p-ONE-mCPP and p-ONE-TRZ have
low or moderately low LUMO-HOMO energy differences meaning that they
would be kinetically labile. Two other metabolites NEF-ONE and
p-OH-TRZ also have low LUMO-HOMO energy differences so that they also
would be kinetically labile. The kinetic lability and the presence of
electron-deficient regions on the surfaces of NEF-ONE, p-ONE-NEF,
p-mCPP and p-ONE-TRZ mean that the metabolites can indeed react
readily with the cellular antioxidant glutathione resulting into
glutathione depletion and hence oxidative stress and cellular
toxicity, and may also cause oxidation of nucleobases and hence DNA
damage. Thus, molecular modelling analyses provide support to the
idea that cellular toxicity due to NEF and its metabolites may be
mediated by quinone-imine and other ketonic species.
Key words:
Nefazodone, antidepressant, CYP3A4, mCPP, glutathione, molecular
modelling
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