Abstract des Autors

Selective androgen receptor modulators (SARMs) are drugs designed to have tissue-specific activation of the receptor to increase muscle mass and bone density, while avoiding potential negative side effects in other tissues, such as prostate enlargement. LGD-4033 is a nonsteroidal, oral SARM recently developed by Ligand Pharmaceuticals. In clinical trials it was shown to promote a dose-dependent increase in lean body mass after 21 days of treatment, with no significant change in prostate-specific antigen concentrations. While the drug is not approved for use and is not yet available from the pharmaceutical company, there are several websites claiming to sell the product. The presence of LGD-4033 with the structure 4-(2-(2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile was confirmed in two products purchased from the Internet in two different laboratories. Additionally, the drug was identified in vials confiscated by the German Bureau of Customs Investigation from 2010 to 2013. In the past year, five human samples have been confirmed to contain the drug in the USA, as well as one sample confirmed in Canada. These observations suggest that abuse of the drug may be significant and anti-doping laboratories should include it in their routine screens. Knowledge of the metabolites excreted into urine could further improve the window of detection for LGD-4033. Thevis et al. identified five hydroxylated metabolites of LGD-4033 produced in human liver microsomes. Alternatively, Geldof et al. identified five different metabolites produced in human liver microsomes, including hydroxylation with double-bond formation, hydroxylation with pyrrolidine ring cleavage, dihydroxylation, and methoxylation. Using fungal metabolism and electrochemical metabolism simulation, Thevis et al. were able to scale-up production of two of the metabolites which allowed structural confirmation by nuclear magnetic resonance (NMR) spectroscopy. While human liver microsomes are frequently used to characterize potential metabolites, the metabolites produced in vivo and the relative abundance of each may differ from in vitro results. Currently, there are no published studies of LGD-4033 metabolites in human urine samples. In the following report, we describe the metabolites identified in four human urine samples and compared them to the published in vitro results. We also identified the metabolites that had the best combination of response and relative abundance that should be included in anti-doping screens to improve the window of detection for the drug. (aus der Einleitung, geändert)