Assessing human urinary clomiphene metabolites after consumption of eggs from clomiphene-treated laying hens using chromatographic-mass spectrometric approaches

Euler, Luisa; Gillard, Nathalie; Delahaut, Philippe; Pierret, Gilles; Mürdter, Thomas E.; Schwab, Matthias; Döhmen, Georg; Thomas, Andreas; Thevis, Mario

doi:10.1016/j.aca.2022.339661

Cited by 10 publications

(16 citation statements)

References 20 publications

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“…101 Clomifene alone accounted for 17% of these findings, and concerns as to potential contamination scenarios arguably originating from clomifene-fed laying hens were raised. The fact that clomifene administrations to laying hens resulted in μg amounts of the drug (and its hydroxylated metabolite) in eggs was confirmed previously, and whether or not the consumption of such eggs could result in AAFs and how such contamination scenarios are to be differentiated from drug abuse was assessed by Euler et al 75 abundance, the cysteine conjugate and the N-acetylated species of acetazolamide were identified. 77 Further investigations, especially the comparison of metabolite profiles following microdoses (simulating contamination scenarios) and cessation of therapeutic settings, appear warranted to assess the utility of these metabolites in sports drug testing.…”

Section: β 2 -Agonists Hormone and Metabolic Modulators And Diureticssupporting

confidence: 55%

“…Clomifene alone accounted for 17% of these findings, and concerns as to potential contamination scenarios arguably originating from clomifene‐fed laying hens were raised. The fact that clomifene administrations to laying hens resulted in μg amounts of the drug (and its hydroxylated metabolite) in eggs was confirmed previously, and whether or not the consumption of such eggs could result in AAFs and how such contamination scenarios are to be differentiated from drug abuse was assessed by Euler et al 75 Study volunteers ingested two eggs obtained from feeding experiments and containing approximately 10–20 μg of clomifene each, and post‐ingestion urine specimens were analyzed for the intact drug as well as its metabolites using LC–HRMS/MS. Also, pharmaceutical‐grade clomifene was microdosed and urine collected in accordance with the egg consumption study.…”

Section: β2‐agonists Hormone and Metabolic Modulators And Diureticsmentioning

confidence: 53%

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Annual banned‐substance review—Analytical approaches in human sports drug testing 2021/2022–

Thevis

Kuuranne

Geyer

2022

Drug Testing and Analysis

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Also in 2021/2022, considerable efforts were invested into advancing human sports drug testing programs, recognizing and taking into account existing as well as emerging challenges in anti-doping, especially with regard to substances and methods of doping specified in the World Anti-Doping Agency's 2022 Prohibited List. In this edition of the annual banned-substance review, literature on recent developments published between October 2021 and September 2022 is summarized and discussed.Focus is put particularly on enhanced analytical approaches and complementary testing options in human doping controls, appreciating the exigence and mission in anti-doping and, equally, the contemporary "new normal" considering, for example, the athlete's exposome versus analytical sensitivity and applicable anti-doping regulations for result interpretation and management.

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Section: β 2 -Agonists Hormone and Metabolic Modulators And Diureticssupporting

confidence: 55%

Section: β2‐agonists Hormone and Metabolic Modulators And Diureticsmentioning

confidence: 53%

Annual banned‐substance review—Analytical approaches in human sports drug testing 2021/2022–

Thevis

Kuuranne

Geyer

2022

Drug Testing and Analysis

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“…If not otherwise specified, the presence of a prohibited substance (or its metabolite) constitutes an adverse analytical finding (AAF) in doping controls, and whether the detection of trace amounts of banned substances originates from deliberate doping has been argued in various cases in the past. 17 Contaminated food or food additives were shown to be a potential source of unintentional doping, [18][19][20][21] with the illegal use of clenbuterol in farming being presumably the most notorious example for this scenario. 22,23 Due to the risk of zilpaterol residues in meat, a minimum reporting level (MRL) of 5 ng/mL in urine was established by WADA in 2021, 24 and the detection of the drug at concentrations above this level is to be reported by anti-doping laboratories as AAFs.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Determination and enantioselective separation of zilpaterol in human urine after mimicking consumption of contaminated meat using high‐performance liquid chromatography with tandem mass spectrometry techniques

Euler

Wagener

Thomas

et al. 2022

Rapid Comm Mass Spectrometry

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Rationale: The synthetic β-adrenoreceptor agonist zilpaterol is legitimately used as an animal feed supplement in selected countries due to its known effects on lipolysis and protein biosynthesis. These pharmacological characteristics of zilpaterol have contributed to its classification as doping agent in sport by the World Anti-Doping Agency. However, the use as a feed supplement can lead to residues of the drug in edible tissues and, possibly, also in the urine of consumers.Methods: To provide urinary elimination profiles of microdosed zilpaterol and to determine whether the ingestion of zilpaterol below or at the acceptable daily intake level of 0.04 μg/kg bodyweight can result in an adverse analytical finding (AAF) in doping controls, healthy volunteers were administered single or multiple oral doses of 0.5 μg or 3 μg zilpaterol to mimic ingestion of contaminated cattle meat. Urine samples were collected and analyzed using a validated high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/ MS) method and a newly developed chiral high-performance liquid chromatographyatmospheric pressure chemical ionization-tandem mass spectrometry (HPLC-APCI-MS/MS) method.Results: Urinary peak concentrations of zilpaterol were observed for all volunteers 1.5-12.5 h after ingestion, and maximum levels >5 ng/mL, which would constitute an AAF in doping controls, were found after the intake of 3 μg of zilpaterol on five consecutive days in one out of five study participants. Noteworthy, the enantiomeric ratio of excreted zilpaterol remained constant over time. Conclusion:This study provides first insights into the urinary excretion of microdosed zilpaterol. Furthermore, a method was successfully developed and applied for the separation of the zilpaterol enantiomers with mass spectrometric detection.

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“…by taking clomiphene oral liquid, but the residues of clomiphene were found in their eggs (Euler et al, 2022). To prevent human health from being affected by the ingestion of clomiphene, trimetazidine, and meldonium, a detection method is required to screen out the preparations containing these compounds.…”

mentioning

confidence: 99%

Solid phase extraction-high performance liquid chromatography-tandem mass spectrometry three metabolic regulators in food: clomiphene, trimetazidine, and meldonium

Wang¹,

Wang²,

Shi³

et al. 2022

Preprint

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Clomiphene, trimetazidine, and meldonium are three common clinical drugs, and long-term consumption will cause damage to human health. Currently, animal-derived food contamination is a major concern, and these compounds have a high probability of entering the human body and remaining there for a long time. In this study, a liquid chromatography-tandem triple quadrupole mass spectrometry method was developed to determine the residues of three metabolic regulators in food. With 0.1% formic acid water-acetonitrile solution (25:75, V/V), samples were extracted ultrasonically. After MCX SPE Column Cleanup, the Shiseido PC HILIC column was used for separation, with positive ion multiple reaction monitoring mode monitoring and isotope internal standard method used for quantifying. In this optimized condition, both clomiphene and trimetazidine had detection limits of 0.25 µg/kg and quantification limits of 0.5 µg/kg. Meldonium had a detection limit of 2.5 µg/kg and a quantification limit of 5.0 µg/kg. Recovery rates ranged from 80.1–119.9%, and precision RSD was 1.95–15.4% (n = 6). This method is suitable for detecting food containing clomiphene, trimetazidine, and mildronium.

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Assessing human urinary clomiphene metabolites after consumption of eggs from clomiphene-treated laying hens using chromatographic-mass spectrometric approaches

Cited by 10 publications

References 20 publications

Annual banned‐substance review—Analytical approaches in human sports drug testing 2021/2022–

Annual banned‐substance review—Analytical approaches in human sports drug testing 2021/2022–

Determination and enantioselective separation of zilpaterol in human urine after mimicking consumption of contaminated meat using high‐performance liquid chromatography with tandem mass spectrometry techniques

Solid phase extraction-high performance liquid chromatography-tandem mass spectrometry three metabolic regulators in food: clomiphene, trimetazidine, and meldonium

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