Fazlul Huq, Deena Ababneh and Ali Alshehri

Discipline of Biomedical Science, Faculty of Medicine, The University of Sydney

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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 9520

E-mail : F.Huq@usyd.edu.au.

Abstract

Carbamazepine (CBZ) is an important drug that has replaced both phenytoin and phenobarbitone as the first-line anticonvulsant for a number of paediatric seizure disorders. CBZ undergoes extensive hepatitic metabolism catalysed by cytochrome P450 enzyme system. Thirty-three metabolites of CBZ have been identified. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that the metabolites HIM, IM, IMQ, 9-ACA and AI have low LUMO-HOMO energy differences so that they would be kinetically labile. The presence of both electron-rich and electron-deficient regions on the surface of CBZ and its metabolites indicate that they may be subject to both electrophilic and nucleophilic attacks. This means that the reactive metabolites especially 9-ACA and AI can react readily with electron-rich molecules such as reduced form of glutathione and nucleobases in DNA, thus causing cellular toxicity and DNA damage respectively.

Key words: Carbamazepine, Tegretol, epilepsy, CYP3A, aplastic anaemia, molecular modelling

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