5- Molecular modelling analysis of the metabolism of lumiracoxib

Fazlul Huq

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

C42, 75 East Street, PO Box 170, Lidcombe, NSW 1825, Australia.

Phone: 061 2 9351 9522; Fax: 061 2 9351 9520 Email: f.huq@fhs.usyd.edu.au

Lumiracoxib (LUM) is a selective COX-2 inhibitor used for the treatment of osteoarthritis, rheumatoid arthritis and acute pain. It is chemically distinct from other COX-2 selective inhibitors in having a carboxyl group that makes it weakly acidic. It has good oral bioavailability of the order of 74% and is rapidly absorbed reaching maximum plasma concentrations within 2 h after intake and is highly bound to plasma proteins. It has short elimination half-life from plasma of about 4 h. LUM is extensively metabolized by hepatic CYP2C9 to produce over twenty different metabolites. The major pathways include oxidation of the 5-methyl group and/or hydroxylation of the dihaloaromatic ring. The oxidative pathways are catalyzed primarily by CYP2C9 with minor contributions from CYP1A2 and CYP2C9. LUM undergoes extensive metabolism in humans.

Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that LUM and its metabolites have moderately large LUMO-HOMO energy differences ranging from 4.62 eV to 5.07 eV from DFT calculations. Thus, although the molecular surfaces of LUM and its metabolites have some electron-deficient regions, the rates of their reaction with cellular nucleophiles such as glutathione, and nucleobases in DNA are expected to be low. This means that any induction of cellular toxicity associated with oxidative stress and DNA damage associated with oxidation of nucleobases may also be low.

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