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In vitro metabolite profiling of sildenafil based on metabolomics approach
Author(s) -
Kim Sunjoo,
Jo Jun Hyun,
Kwon Oh Kwang,
Lee Sangkyu
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.669.4
Subject(s) - metabolomics , metabolite , microsome , drug metabolism , hydroxylation , cyp3a4 , chemistry , pharmacology , xenobiotic , sildenafil , metabolism , cytochrome p450 , biochemistry , in vitro , biology , medicine , chromatography , enzyme
Metabolomics combined with high‐resolution mass spectrometry (HR‐MS) and multivariate data analysis has broad applications in the study of xenobiotic metabolism. Although xenobiotic metabolism is essential to understand toxicity, pharmacokinetic parameters, and excretion pathways, it cannot predict all generated metabolites in biological fluids. In the present study, we used a metabolomics approach to further understand sildenafil phase 1 metabolism in human liver microsomes. Twelve phase 1 metabolites were identified in human liver microsomes, of which, M1–M5 were previously known. The chemical structures of novel metabolites were elucidated by MS 2 fragmentation using HR‐MS as follows: M6, reduced sildenafil, M7, N , N ‐deethylation and mono‐oxidation; M8, demethanamine, N , N ‐deethylation and mono‐hydroxylation; M9, demethanamine and N , N ‐deethylation; M10 and M11, mono‐oxidation in the piperazine ring after N ‐demethylation; and M12, mono‐oxidation. All metabolites except M1 were formed by CYP3A4 and 3A5. In conclusion, we successfully updated the metabolic pathway of sildenafil in the human liver, including seven novel metabolites, using metabolomics combined with HR‐MS and multivariate data analysis. Support or Funding Information BK21 Plus KNU Multi‐Omics based Creative Drug Research Team