title: 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 μM) 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 μM) 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.
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National Univerity, Daegu 702-701, Republic of Korea.
authors.forename: Sang Kyu
authors.initials: SK
authors.lastname: Lee
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Kim
authors.forename: Hye Hyun
authors.initials: HH
authors.lastname: Yoo
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D004285:Dogs; D000882:Haplorhini; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods*; D051379:Mice; D008862:Microsomes, Liver / Q000737:chemistry* / Q000378:metabolism; D015999:Multivariate Analysis; D010879:Piperazines / Q000378:metabolism*; D011687:Purines / Q000378:metabolism; D051381:Rats; D000068677:Sildenafil Citrate; D013045:Species Specificity; D013450:Sulfones / Q000378:metabolism*
chemical_list: D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate