5- Molecular modelling analysis of the metabolism of duloxetine

 Fazlul Huq

 Discipline of Biomedical Science, Faculty of Medicine, The University of Sydney, Email: F.Huq@usyd.edu.au

Duloxetine HCl (DX; LY248686) is a potent and balanced dual reuptake inhibitor of norepinephrine and serotonin, used in the treatment of depression, peripheral diabetic neuropathic pain and female stress urinary incontinence. However, treatment with DX is frequently associated with such adverse effects as nausea, dry mouth, fatigue, insomnia and constipation although serious adverse effects are rare. The oxidative metabolism of DX is catalyzed by CYP3A, CYP1A2, CYP2C9, CYP2C19 and CYP2D6. Metabolism of DX by CYP1A2, CYP2C9 and CYP2D6 produces a risk of interactions with other drugs that share these metabolic pathways. Molecular modelling analyses based on semi-empirical and DFT calculations show that DX and its metabolites have LUMO-HOMO energy differences ranging from 4.08 and 4.63 eV obtained from DFT calculations. The values suggest neither DX nor its metabolites would be highly inert or extremely labile. Thus, although the molecular surfaces of DX and its metabolites have some electron-deficient regions so that they could potentially react with glutathione and nucleobases in DNA, relative kinetic inertness of the molecules means that the rates of such adverse reactions would be low.

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