Massenspektrometrischer Nachweis und Metabolismus von selektiven Androgenrezeptor-Modulatoren in der präventiven Dopingforschung

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In the presented dissertation, liquid chromatography and mass spectrometric detection were used to investigate the metabolism and excretion behavior of the selective androgen receptor modulators LGD-4033 and RAD140. SARMs are prohibited by the World Anti-Doping Agency due to their performance enhancing effect. Micro-dose excretion studies were performed with both SARMs to simulate the intake of minute amounts of SARMs by ingestion of contaminated dietary supplements. Using high performance liquid chromatography coupled to high resolution tandem mass spectrometry powerful methods were developed and characterized to detect the substances. For LGD-4033, a method to estimate the time of intake and dose was developed. For this, the relationship between a metabolite ratio and time between intake of the substance and collection of the sample was employed. For the SARM RAD140 multiple metabolites were identified for the first time in human excretion samples. The acquired data of excretion behavior could help in case result management of positive doping control samples containing RAD140 in the future. As for LGD-4033, the metabolite ratios of RAD140 were investigated in regards to their application for predicting the time of RAD140-intake. Tentative ratio threshold values were proposed to estimate the time of intake.
Additionally, different in vitro techniques were employed and compared in regards their applicability to generate metabolites of RAD140 for doping control purposes. For this, RAD140 was transformed using subcellular liver fractions, electrochemical oxidation and liver cell spheroids in an organ-on-a-chip platform. The resulting metabolites were compared to a doping control sample containing RAD140, which was cleared for research purposes. During this investigation, six novel metabolites were detected and described. The highest number of metabolites were detected in the samples of the organ-on-a-chip experiment, the incubation with liver fractions yielded a high number of RAD140 metabolites as well. Due to the lower workload of the liver fractions, both approaches were deemed suitable for the in vitro generation of metabolites of RAD140. The electrochemical oxidation resulted in the lowest number of metabolites, but could be used to generate larger amounts of metabolites for further studies.
This dissertation expands the analytical knowledge about the detection and metabolism of the investigated SARMs and lays the groundwork for further investigations.
Original languageGerman
Place of PublicationKöln
PublisherDeutsche Sporthochschule Köln
Number of pages42
Publication statusPublished - 2023