کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
7615602 1493994 2018 29 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Non-targeted metabolomics-guided sildenafil metabolism study in human liver microsomes
ترجمه فارسی عنوان
متابولیسم سیلدنافیل هدایت شده توسط متابولومیک غیر هدفمند در میکروسوم های کبدی انسانی
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آنالیزی یا شیمی تجزیه
چکیده انگلیسی
Metabolomics combined with high-resolution mass spectrometry (HR-MS) and multivariate data analysis has broad applications in the study of xenobiotic metabolism. Although information about xenobiotic metabolism is essential to understand toxic mechanisms, pharmacokinetic parameters and excretion pathways, it is limited to predict all generated metabolites in biological fluids. Here, we revisited sildenafil metabolism in human liver microsomes using a metabolomics approach to achieve a global picture of sildenafil phase 1 metabolism. Finally, 12 phase 1 metabolites were identified in human liver microsomes; M1-M5 were previously known metabolites. The chemical structures of the novel metabolites were elucidated by MS2 fragmentation using an HR-MS system 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 CYP3A5. In conclusion, we successfully updated the metabolic pathway of sildenafil in human liver, including 7 novel metabolites using metabolomics combined with HR-MS and multivariate data analysis.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Chromatography B - Volume 1072, 1 January 2018, Pages 86-93
نویسندگان
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