Mass spectrometric characterization of urinary toremifene metabolites for doping control analyses

Gómez, Cristina; Pozo, Óscar J.; Díaz, Ramón; Sancho, Juan V.; Vilaroca, E.; Salvador, J.‐Pablo; Marco, M.‐Pilar; Hernández, Félix; Segura, Jordi; Ventura, Rosa

doi:10.1016/j.chroma.2011.05.073

Cited by 23 publications

(30 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The metabolites M1 and M3, respectively, having a protonated molecular ion [M + H] + at m/z 404 and 434, gave a characteristic fragment ion at m/z 58 and 88 indicating loss of one methyl group and gain of an oxygen atom from a N,N ‐dimethylethaneamine group ( m/z 72) (Figures B and D), whereas that of GSK5182 showed a fragment ion at m/z 72 (Figure A). Similarly, the MS/MS spectrum of M1 and M3 collision‐induced fragmented protonated ions gave m/z 152 and 182, whereas that of GSK5182 showed a fragment ion at m/z 166, which was also observed in the MS/MS spectrum of toremifene , a structural analog of GSK5182. Based on these results, M1 and M3 were identified as N ‐desmethyl‐GSK5182 and GSK5182 N ‐oxide, respectively.…”

Section: Resultsmentioning

confidence: 64%

In vitro metabolism of an estrogen‐related receptor γ modulator, GSK5182, by human liver microsomes and recombinant cytochrome P450s

Joo

Lee

et al. 2015

Biopharm & Drug Disp

View full text Add to dashboard Cite

GSK5182 (4-[(Z)-1-[4-(2-dimethylaminoethyloxy)phenyl]-hydroxy-2-phenylpent-1-enyl]phenol) is a specific inverse agonist for estrogen-related receptor γ, a member of the orphan nuclear receptor family that has important functions in development and homeostasis. This study was performed to elucidate the metabolites of GSK5182 and to characterize the enzymes involved in its metabolism. Incubation of human liver microsomes with GSK5182 in the presence of NADPH resulted in the formation of three metabolites, M1, M2 and M3. M1 and M3 were identified as N-desmethyl-GSK5182 and GSK5182 N-oxide, respectively, on the basis of liquid chromatography-tandem mass spectrometric (LC-MS/MS) analysis. M2 was suggested to be hydroxy-GSK5182 through interpretation of its MS/MS fragmentation pattern. In addition, the specific cytochrome P450 (P450) and flavin-containing monooxygenase (FMO) isoforms responsible for GSK5182 oxidation to the three metabolites were identified using a combination of correlation analysis, chemical inhibition in human liver microsomes and metabolism by expressed recombinant P450 and FMO isoforms. GSK5182 N-demethylation and hydroxylation is mainly mediated by CYP3A4, whereas FMO1 and FMO3 contribute to the formation of GSK5182 N-oxide from GSK5182. The present data will be useful for understanding the pharmacokinetics and drug interactions of GSK5182 in vivo.

show abstract

Section: Resultsmentioning

confidence: 64%

In vitro metabolism of an estrogen‐related receptor γ modulator, GSK5182, by human liver microsomes and recombinant cytochrome P450s

Joo

Lee

et al. 2015

Biopharm & Drug Disp

View full text Add to dashboard Cite

show abstract

“…Both studies yielded comparable results however, the dehalogenated and bisoxidized metabolite with the determined elemental composition of C 26 H 27 NO 3 (mol wt = 401.1991) was detected in all fractions (unconjugated, glucuronide, and sulfate) in the study by Mazzarino et al . but only unconjugated in the report by Gomez et al . Further, alternative options as to the structure of this metabolite were discussed being possibly a carboxylated or a lactone derivative of tamoxifen.…”

Section: Hormone Antagonists and Modulatorsmentioning

confidence: 84%

Annual banned‐substance review: analytical approaches in human sports drug testing

Thevis

Kuuranne

Geyer

et al. 2012

Drug Testing and Analysis

View full text Add to dashboard Cite

a International anti-doping efforts are harmonized and regulated under the umbrella of the World Anti-Doping Code and the corresponding Prohibited List, issued annually by the World Anti-Doping Agency (WADA). The necessity for a frequent and timely update of the Prohibited List (as the result of a comprehensive consultation process and subsequent consensual agreement by expert panels regarding substances and methods of performance manipulation in sports) is due to the constantly growing market of emerging therapeutics and thus new options for cheating athletes to illicitly enhance performance. In addition, 'tailor-made' substances arguably designed to undermine sports drug testing procedures are considered and the potential of established drugs to represent a doping substance is revisited in light of recently generated information. The purpose of the annual banned substance review is to support doping controls by reporting emerging and advancing methods dedicated to the detection of known and recently outlawed substances. This review surveys new and/or enhanced procedures and techniques of doping analysis together with information relevant to doping controls that has been published in the literature between October

show abstract

“…In summary, despite the use of CID MS/MS experiments with precursor ion isolation in different collision energy conditions, poor fragmentation was observed for TMX and its metabolites, which caused serious difficulties in elucidating the structure of the metabolites detected. These results are consistent with previous data from a TMX derivative (toremifene), which only exhibited m / z 72 and m / z 58 as products ions, the rest of fragment ions being detected during MS/MS experiments with poor abundances (Gómez et al ., ).…”

Section: Resultsmentioning

confidence: 99%

Study of tamoxifen urinary metabolites in rat by ultra‐high‐performance liquid chromatography time‐of‐flight mass spectrometry

Domínguez-Romero

García-Reyes

Beneito‐Cambra

et al. 2015

Biomedical Chromatography

View full text Add to dashboard Cite

Tamoxifen (TMX) is a nonsteroidal estrogen antagonist drug used for the treatment of breast cancer. It is also included in the list of banned substances of the World Anti Doping Agency (WADA) prohibited in and out of competition. In this work, the excretion of urinary metabolites of TMX after a single therapeutic dose administration in rats has been studied using ultra-high-performance liquid chromatography electrospray time-of-flight mass spectrometry (UHPLC-TOFMS). A systematic strategy based on the search of typical biotransformations that a xenobiotic can undergo in living organisms, based on their corresponding molecular formula modification and accurate mass shifts, was applied for the identification of TMX metabolites. Prior to UHPLC-TOFMS analyses, a solid-phase extraction step with polymeric cartridges was applied to urine samples. Up to 38 TMX metabolites were detected. Additional collision induced dissociation (CID) MS/MS fragmentation was performed using UHPLC-QTOFMS. Compared with recent previous studies in human urine and plasma, new metabolites have been reported for the first time in urine. Metabolites identified in rat urine include the oxygen addition, owing to different possibilities for the hydroxylation of the rings in different positions (m/z 388.2271), the incorporation of two oxygen atoms (m/z 404.2220) (including dihydroxylated derivatives or alternatives such as epoxidation plus hydroxylation or N-oxidation and hydroxylation), epoxide formation or hydroxylation and dehydrogenation [m/z 386.2114 (+O -H2 )], hydroxylation of the ring accompanied by N-desmethylation (m/z 374.2115), combined hydroxylation and methoxylation (m/z 418.2377), desaturated TMX derivate (m/z 370.2165) and its N-desmethylated derivate (m/z 356.2009), the two latter modifications not previously being reported in urine. These findings confirm the usefulness of the proposed approach based on UHPLC-TOFMS.

show abstract

Mass spectrometric characterization of urinary toremifene metabolites for doping control analyses

Cited by 23 publications

References 44 publications

In vitro metabolism of an estrogen‐related receptor γ modulator, GSK5182, by human liver microsomes and recombinant cytochrome P450s

In vitro metabolism of an estrogen‐related receptor γ modulator, GSK5182, by human liver microsomes and recombinant cytochrome P450s

Annual banned‐substance review: analytical approaches in human sports drug testing

Study of tamoxifen urinary metabolites in rat by ultra‐high‐performance liquid chromatography time‐of‐flight mass spectrometry

Contact Info

Product

Resources

About