5. Molecular modelling analysis of the metabolism of sildenafil

Fazlul Huq

School of Biomedical Sciences, Faculty of Health Sciences, The University of Sydney

Abstract:

Sildenafil citrate, commonly known as VIAGRA^®, is highly effective in treating erectile dysfunction. However, it has a number of side effects including headache, flushing, abnormal dreams, dyspepsia and a coloured tinge associated with vision. Also, the use of the drug has been reported to be associated with myocardial infarction, sudden cardiac arrest, ventricular arrhythmia, transient ischaemic attack and hypertension. The drug is metabolized primarily in liver by cytochrome P450 isoforms CYP3A4 and CYP2C9. Sixteen different metabolites have been isolated in man and animal models. In general, the metabolism of sildenafil appears to involve piperazine ring, either via N-demethylation, hydroxylation or ring opening. The major metabolite of sildenafil is UK-103,320 that is formed from N-demethylation of sildenafil. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that sildenafil and its metabolites are moderately labile kinetically and may be subject to electrophilic attack at a number of sites. The metabolites UK-95,340, M6 and UK-332,012 have marginally lower LUMO-HOMO energy differences than sildenafil and other metabolites indicating that they would be more labile kinetically. However, none of the metabolites of sildenafil is expected to be extremely labile and therefore none would be extremely toxic. This gives credence to the idea that, taken under proper conditions, sildenafil would be quite safe in the treatment of erectile dysfunction.

Key words: VIAGRA^®, erectile dysfunction, UK-103,320, metabolism, molecular modelling

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