Identification and synthesis of (Z)-3'-hydroxy clomiphene as a new potential doping-relevant metabolite of clomiphene.
Journal
Rapid communications in mass spectrometry : RCM
ISSN: 1097-0231
Titre abrégé: Rapid Commun Mass Spectrom
Pays: England
ID NLM: 8802365
Informations de publication
Date de publication:
15 Sep 2023
15 Sep 2023
Historique:
revised:
14
06
2023
received:
24
05
2023
accepted:
14
06
2023
medline:
16
8
2023
pubmed:
15
8
2023
entrez:
14
8
2023
Statut:
ppublish
Résumé
A recent study addressed the possibility of unintentional ingestion of clomiphene through residues in chicken eggs. The method developed here helped distinguish between microdose intake of (E/Z)-clomiphene citrate and consumption of clomiphene-containing eggs by the urinary pattern of four mono-hydroxylated clomiphene metabolites. However, reanalyses of doping-control samples, which showed an adverse analytical finding for clomiphene, revealed a hydroxy clomiphene (HC) isomer that was not found after microdose intake or after consumption of clomiphene-containing eggs and could not be assigned to any of the available reference compounds. The aim of the present follow-up study was to identify this HC isomer and to characterize this metabolite with respect to its potential properties as long-term metabolite in doping controls. (E/Z)-3'-HC and (E/Z)-4'-HC were synthesized involving the McMurry reaction. An ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and optimized after a derivatization step with dansyl chloride to separate eight HC isomers. Using this method, urine samples from a controlled clomiphene administration study were analyzed, in which male study participants received therapeutic doses of clomiphene for 30 days and collected urine samples for up to 8 months. Thus, isomer-specific HC elimination profiles could be monitored. The metabolite previously found in doping-control samples was identified as (Z)-3'-HC. The elimination profiles of the different HCs confirmed previous results, with (Z)-3-HC being the most abundant urinary hydroxy metabolite shortly after administration. A new finding was that the data suggest that (Z)-3'-HC is excreted at higher relative concentrations only several weeks after drug intake. These findings might be of particular importance in sport drug testing as they can assist in the decision-making process to distinguish between intentional doping and inadvertent exposure to clomiphene via food contamination.
Substances chimiques
Clomiphene
1HRS458QU2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e9599Subventions
Organisme : Manfred-Donike Institute for Doping Analysis
Organisme : Federal Ministry of the Interior of the Federal Republic of Germany
Organisme : Robert Bosch Stiftung, Stuttgart, Germany
Organisme : Partnership for Clean Competition
Informations de copyright
© 2023 The Authors. Rapid Communications in Mass Spectrometry published by John Wiley & Sons Ltd.
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