Detection of novel metabolite for Roxadustat doping by global metabolomics.

Abstract:

:Roxadustat (FG-4592, Rox) is a stabilizer for hypoxia-inducible transcription factors (HIFs), which induce production of the erythroid growth factor erythropoietin, and has been listed by the World Anti-Doping Agency as a prohibited substance for athletes since 2011. Although the detection technologies for Rox and its glucuronide-conjugated metabolite (Rox-Gluc) have been developed exploiting triple quadrupole mass spectrometry (MS/MS), the production of metabolites from Rox in the human body remains to be clarified. Here, we established a protocol for the detection of unknown metabolites in plasma and urine samples from Rox-doping mice by global metabolomics using an ultra high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF/MS). We identified methylated Rox (Rox-Methyl), a novel metabolite, and Rox-Gluc in mouse urine by principal component analysis and orthogonal partial least squares discriminant analysis based on detected features by UHPLC-QTOF/MS analysis. The estimated pharmacokinetic parameters of Rox-Methyl and Rox-Gluc in mouse plasma showed similar profiles to that of Rox and both compounds showed similar biological activities. Of note, Rox-Methyl showed shorter half-life than Rox-Gluc in vivo, implying the easy escape from anti-doping screen. These results demonstrate that the global metabolomics method introduced in this study will contribute to the identification and detection of HIF-analog doping.

journal_name

J Biochem

journal_title

Journal of biochemistry

authors

Saigusa D,Suzuki N,Matsumoto Y,Umeda K,Tomioka Y,Koshiba S,Yamamoto M

doi

10.1093/jb/mvy028

subject

Has Abstract

pub_date

2018-02-09 00:00:00

eissn

0021-924X

issn

1756-2651

pii

4847795

pub_type

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