Comparative metabolism of sildenafil in liver microsomes of different species by using LC/MS-based multivariate analysis

Abstract

Sildenafil metabolism in liver microsomes obtained from different species was studied in vitro and compared using liquid chromatography-mass spectrometry (LC/MS) and multivariate statistical analysis. Sildenafil (1, 5, and 25 mu M) was incubated with rat, mouse, dog, monkey, and human liver microsomes along with NADPH, and the reaction mixtures were analyzed by LC/MS to obtain species-specific metabolic profiles of sildenafil. A total of 12 metabolites were detected and their peak area ratio values were used as variables for multivariate analyses to evaluate the interspecies differences in sildenafil metabolism. Principal components analysis of the metabolic profiles showed that the mouse samples were generally clustered closer to the human samples on the principal component score plot. Similarity index (SI) indicated that sildenafil metabolism in mice, compared to the other animals, was highly analogous (SI = 0.764 at 25 mu M) to that in humans. These results suggest that LC/MS-based multivariate analytical approaches are useful for the evaluation of interspecies differences in the metabolism of xenobiotics. (C) 2011 Elsevier B.V. All rights reserved.