Equine in vivo-derived metabolites of the SARM LGD-4033 and comparison with human and fungal metabolites.
Abstract: LGD-4033 has been found in human doping control samples and has the potential for illicit use in racehorses as well. It belongs to the pharmacological class of selective androgen receptor modulators (SARMs) and can stimulate muscle growth, much like anabolic steroids. However, SARMs have shown superior side effect profiles compared to anabolic steroids, which arguably makes them attractive for use by individuals seeking an unfair advantage over their competitors. The purpose of this study was to investigate the metabolites formed from LGD-4033 in the horse in order to find suitable analytical targets for doping controls. LGD-4033 was administered to three horses after which plasma and urine samples were collected and analyzed for metabolites using ultra high performance liquid chromatography coupled to a high resolution mass spectrometer. In horse urine, eight metabolites, both phase I and phase II, were observed most of which had not been described in other metabolic systems. Six of these were also detected in plasma. The parent compound was detected in plasma, but not in non-hydrolyzed urine. The longest detection times were observed for unchanged LGD-4033 in plasma and in urine hydrolyzed with β-glucuronidase and is thus suggested as the analytical target for doping control in the horse. The metabolite profile determined in the horse samples was also compared to those of human urine and fungal incubate from Cunninghamella elegans. The main human metabolite, dihydroxylated LGD-4033, was detected in the horse samples and was also produced by the fungus. However, it was a not a major metabolite for horse and fungus, which highlights the importance of performing metabolism studies in the species of interest.
Copyright © 2017 Elsevier B.V. All rights reserved.
Publication Date: 2017-12-07 PubMed ID: 29334634DOI: 10.1016/j.jchromb.2017.12.010Google Scholar: Lookup
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- Journal Article
Summary
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The research study investigates the metabolites formed from LGD-4033 in horses to find suitable analytical targets for doping controls. This selective androgen receptor modulator (SARM) has the potential to illicitly enhance muscle growth in racehorses and has been found in human doping samples.
Background
- The study focuses on LGD-4033, a member of the Selective Androgen Receptor Modulators (SARMs) class of drugs. Like anabolic steroids, SARMs can stimulate muscle growth and are therefore potentially used for illicit performance enhancement in sports such as horse racing.
- Unlike anabolic steroids, SARMs have shown to have superior side effect profiles, making them more attractive for individuals seeking an unfair advantage over their competitors.
- The drug has previously been detected in human doping control samples, indicating its use among athletes.
Objective and Methodology
- The primary objective of the study is to investigate the metabolites formed from LGD-4033 in horses, in order to identify suitable analytical targets for doping controls in this species.
- To achieve this, LGD-4033 was administered to three horses after which plasma and urine samples were collected and analyzed for metabolites using ultra-high performance liquid chromatography coupled with a high-resolution mass spectrometer.
Findings
- In horse urine, eight metabolites, both phase I and phase II, were observed. Most of these were not previously described in other metabolic systems.
- Six of these metabolites were also detected in plasma. However, the parent compound (LGD-4033) was detected in plasma, but not in non-hydrolyzed urine.
- The longest detection times were observed for unchanged LGD-4033 in plasma and in urine hydrolyzed with β-glucuronidase, making it a potential analytical target for doping control in the horse.
Comparison with Human and Fungal Metabolites
- The researchers also compared the metabolite profile determined in the horse samples with those of human urine and fungal incubate from Cunninghamella elegans.
- The main human metabolite, dihydroxylated LGD-4033, was detected in the horse samples and was also produced by the fungus. Nevertheless, it was not a major metabolite for horse and fungus.
- This significant difference underscores the importance of performing metabolism studies in the species of interest
Cite This Article
APA
Hansson A, Knych H, Stanley S, Berndtson E, Jackson L, Bondesson U, Thevis M, Hedeland M.
(2017).
Equine in vivo-derived metabolites of the SARM LGD-4033 and comparison with human and fungal metabolites.
J Chromatogr B Analyt Technol Biomed Life Sci, 1074-1075, 91-98.
https://doi.org/10.1016/j.jchromb.2017.12.010 Publication
Researcher Affiliations
- Division of Analytical Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, Box 574, SE-75123, Uppsala, Sweden. Electronic address: Annelie.Hansson@farmkemi.uu.se.
- K. L. Maddy Equine Analytical Chemistry Laboratory, School of Veterinary Medicine, University of California, Davis, CA, USA; Department of Veterinary Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA, USA. Electronic address: hkknych@ucdavis.edu.
- K. L. Maddy Equine Analytical Chemistry Laboratory, School of Veterinary Medicine, University of California, Davis, CA, USA. Electronic address: sdstanley@ucdavis.edu.
- Division of Analytical Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, Box 574, SE-75123, Uppsala, Sweden; National Veterinary Institute (SVA), Department of Chemistry, Environment and Feed Hygiene, SE-75651, Uppsala, Sweden. Electronic address: emma.berndtson@gmail.com.
- Division of Analytical Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, Box 574, SE-75123, Uppsala, Sweden; National Veterinary Institute (SVA), Department of Chemistry, Environment and Feed Hygiene, SE-75651, Uppsala, Sweden. Electronic address: liora.jackson@gmail.com.
- Division of Analytical Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, Box 574, SE-75123, Uppsala, Sweden; National Veterinary Institute (SVA), Department of Chemistry, Environment and Feed Hygiene, SE-75651, Uppsala, Sweden. Electronic address: Ulf.Bondesson@sva.se.
- Institute of Biochemistry and Center for Preventive Doping Research, German Sport University, Cologne, Germany. Electronic address: Thevis@dshs-koeln.de.
- Division of Analytical Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, Box 574, SE-75123, Uppsala, Sweden; National Veterinary Institute (SVA), Department of Chemistry, Environment and Feed Hygiene, SE-75651, Uppsala, Sweden. Electronic address: Mikael.Hedeland@sva.se.
MeSH Terms
- Animals
- Cunninghamella / metabolism
- Horses
- Humans
- Limit of Detection
- Nitriles / analysis
- Nitriles / chemistry
- Nitriles / metabolism
- Pyrrolidines / analysis
- Pyrrolidines / chemistry
- Pyrrolidines / metabolism
- Solid Phase Extraction
Citations
This article has been cited 4 times.- Breuer J, Thomas A, Delahaut P, Schänzer W, Geyer H, Thevis M. Investigations into the concentration and metabolite profiles of stanozolol and LGD-4033 in blood plasma and seminal fluid using liquid chromatography high-resolution mass spectrometry.. Anal Bioanal Chem 2023 Feb;415(4):669-681.
- Broberg MN, Knych H, Bondesson U, Pettersson C, Stanley S, Thevis M, Hedeland M. Investigation of Equine In Vivo and In Vitro Derived Metabolites of the Selective Androgen Receptor Modulator (SARM) ACP-105 for Improved Doping Control.. Metabolites 2021 Feb 1;11(2).
- Gadaj A, Ventura E, Healy J, Botrè F, Sterk SS, Buckley T, Mooney MH. Enhanced UHPLC-MS/MS screening of selective androgen receptor modulators following urine hydrolysis.. MethodsX 2020;7:100926.
- Christiansen AR, Lipshultz LI, Hotaling JM, Pastuszak AW. Selective androgen receptor modulators: the future of androgen therapy?. Transl Androl Urol 2020 Mar;9(Suppl 2):S135-S148.
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