title: In vivo metabolic investigation of silodosin using UHPLC-QTOF-MS/MS and in silico toxicological screening of its metabolites.
abstract: Silodosin (SLD) is a novel α1-adrenoceptor antagonist which has shown promising clinical efficacy and safety in patients with benign prostatic hyperplasia (BPH). However, lack of information about metabolism of SLD prompted us to investigate metabolic fate of SLD in rats. To identify in vivo metabolites of SLD, urine, feces and plasma were collected from Sprague-Dawley rats after its oral administration. The samples were prepared using an optimized sample preparation approach involving protein precipitation followed by solid-phase extraction and then subjected to LC/HR-MS/MS analysis. A total of 13 phase I and six phase II metabolites of SLD have been identified in rat urine which includes hydroxylated, N-dealkylated, dehydrogenated, oxidative, glucosylated, glucuronide and N-sulphated metabolites, which are also observed in feces. In plasma, only dehydrogenated, N-dealkylated and unchanged SLD are observed. The structure elucidation of metabolites was done by fragmentation in MS/MS in combination with HRMS data. The potential toxicity profile of SLD and its metabolites were predicted using TOPKAT software and most of the metabolites were proposed to show a certain degree of skin sensitization and occular irritancy. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research, Hyderabad (NIPER-H), Balanagar, Hyderabad, 500037, Telangana, India.
authors.forename: Chiguru
authors.initials: C
authors.lastname: Vishnuvardhan
authors.affiliation: Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research, Hyderabad (NIPER-H), Balanagar, Hyderabad, 500037, Telangana, India.
authors.forename: Saibaba
authors.initials: S
authors.lastname: Baikadi
authors.affiliation: National Center for Mass Spectrometry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500607, Telangana, India.
authors.forename: Roshan M
authors.initials: RM
authors.lastname: Borkar
authors.affiliation: Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research, Hyderabad (NIPER-H), Balanagar, Hyderabad, 500037, Telangana, India. srini@iict.res.in.|National Center for Mass Spectrometry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500607, Telangana, India. srini@iict.res.in.
authors.forename: R
authors.initials: R
authors.lastname: Srinivas
authors.affiliation: Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research, Hyderabad (NIPER-H), Balanagar, Hyderabad, 500037, Telangana, India. satish.niperhyd@gov.in.
authors.forename: N
authors.initials: N
authors.lastname: Satheeshkumar
mesh_terms: D000284:Administration, Oral; D058668:Adrenergic alpha-1 Receptor Antagonists / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003198:Computer Simulation; D006801:Humans; D008658:Inactivation, Metabolic; D007211:Indoles / Q000378:metabolism* / Q000633:toxicity*; D008297:Male; D055432:Metabolomics; D011470:Prostatic Hyperplasia / Q000188:drug therapy; D017207:Rats, Sprague-Dawley; D052616:Solid Phase Extraction; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D007211:Indoles; C095285:silodosin
keywords: LC-QTOF-MS/MS; in silico toxicity; metabolite characterization; silodosin