Source:http://linkedlifedata.com/resource/pubmed/id/21254313
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Predicate | Object |
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
2
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pubmed:dateCreated |
2011-2-15
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pubmed:abstractText |
The metabolic fate of the emerging drug candidate S107, possessing the potential for misuse as performance-enhancing agent in sports, was investigated by in vitro phase I and II experiments with human microsomal and S9 liver enzymes. The metabolites were identified by liquid chromatography-mass spectrometry with electrospray ionisation in positive mode (LC-ESI-MS/MS). Their collision-induced dissociation behaviour was studied by high-resolution/high accuracy Orbitrap MS(n) analysis, supported by stable isotope labelling, H/D-exchange experiments and density functional theory calculations. Monooxygenation accounted for the main phase I metabolic transformation due to N- and S-oxidation of the 1,4-benzothiazepine core, as substantiated by chemical synthesis, selective reduction methods and characteristic APCI in source fragmentation behaviour of the metabolites. Another dominant metabolic pathway was demethylation, yielding the N- and O-demethylated metabolite, respectively. The latter was further conjugated by glucuronidation as well as sulfonation in subsequent phase II metabolic reactions, whereas the N-demethylated metabolite was not amenable to conjugation. The active drug molecule itself was converted to two glucuronic acid conjugates, which are proposed to consist of two quaternary S107-N(+)-glucuronide isomers. All glucuronides were susceptible to enzymatic hydrolysis with ?-glucuronidase (Escherichia coli). A comprehensive LC-ESI-MS(/MS)-based detection method for urine was developed and its fitness for purpose was assessed. The assay can serve as a potential screening and/or confirmation method for S107 in clinical drug testing and doping control analysis in the future.
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pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical | |
pubmed:status |
MEDLINE
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pubmed:month |
Feb
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pubmed:issn |
1096-9888
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pubmed:author | |
pubmed:copyrightInfo |
Copyright © 2011 John Wiley & Sons, Ltd.
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pubmed:issnType |
Electronic
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pubmed:volume |
46
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
112-30
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pubmed:meshHeading |
pubmed-meshheading:21254313-Chromatography, Liquid,
pubmed-meshheading:21254313-Doping in Sports,
pubmed-meshheading:21254313-Female,
pubmed-meshheading:21254313-Humans,
pubmed-meshheading:21254313-Male,
pubmed-meshheading:21254313-Spectrometry, Mass, Electrospray Ionization,
pubmed-meshheading:21254313-Tandem Mass Spectrometry,
pubmed-meshheading:21254313-Thiazepines
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pubmed:year |
2011
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pubmed:articleTitle |
Investigation of the in vitro metabolism of the emerging drug candidate S107 for doping-preventive purposes.
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pubmed:affiliation |
Institute of Biochemistry, Center for Preventive Doping Research, German Sport University Cologne, Cologne, Germany.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Clinical Trial, Phase II,
Clinical Trial, Phase I
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