Equine in vivo metabolite profiling of the selective androgen receptor modulator LGD-3303 for doping control

Malin Nilsson Broberg; Heather Knych; Ulf Bondesson; Curt Pettersson; Börje Tidstedt; Scott Stanley; Mario Thevis; Mikael Hedeland

doi:10.1016/j.jpba.2023.115468

Equine in vivo metabolite profiling of the selective androgen receptor modulator LGD-3303 for doping control

J Pharm Biomed Anal. 2023 Sep 5:233:115468. doi: 10.1016/j.jpba.2023.115468. Epub 2023 May 18.

Authors

Malin Nilsson Broberg¹, Heather Knych², Ulf Bondesson¹, Curt Pettersson¹, Börje Tidstedt³, Scott Stanley⁴, Mario Thevis⁵, Mikael Hedeland⁶

Affiliations

¹ Department of Medicinal Chemistry, Uppsala University, Box 574, 75123 Uppsala Sweden.
² Kenneth L. Maddy Equine Analytical Pharmacology Laboratory, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.
³ Department of Chemistry, Environment and Feed Hygiene, National Veterinary Institute (SVA), 75189 Uppsala, Sweden.
⁴ Gluck Equine Research Center, University of Kentucky, Lexington, KY 40546, USA.
⁵ Institute of Biochemistry, Center for Preventive Doping Research, German Sport University, 50933 Cologne, Germany.
⁶ Department of Medicinal Chemistry, Uppsala University, Box 574, 75123 Uppsala Sweden. Electronic address: mikael.hedeland@ilk.uu.se.

PMID: 37224728
DOI: 10.1016/j.jpba.2023.115468

Abstract

LGD-3303 is a Selective Androgen Receptor Modulator (SARM) that is prohibited in both equine and human sports due to its anabolic properties. The aim of this study was to investigate the equine in vivo metabolite profile of LGD-3303 and identify drug metabolites that can be suitable as new and improved analytical targets for equine doping control. This was performed by an oral administration of 0.05 mg·kg^-1 LGD-3303 to horses, where blood and urine samples were collected up to 96 h after administration. The in vivo samples consisting of plasma, urine and hydrolyzed urine were analyzed utilizing ultra-high performance liquid chromatography hyphenated to a Q Exactive™ Orbitrap™ high resolution mass spectrometer with a heated electrospray ionization source. A total of eight metabolites of LGD-3303 were tentatively identified, including one carboxylated and several hydroxylated metabolites in combination with glucuronic acid conjugates. A monohydroxylated metabolite is suggested as an analytical target for doping control analysis of plasma and urine after hydrolysis with β-glucuronidase, due to the high intensity and prolonged detection time in comparison to parent LGD-3303.

Keywords: Doping control; Equine; LGD-3303; Mass spectrometry; Metabolites; Selective androgen receptor modulator.

MeSH terms

Androgens / urine
Animals
Doping in Sports* / prevention & control
Horses
Receptors, Androgen / metabolism
Substance Abuse Detection / methods

Substances

9-chloro-2-ethyl-1-methyl-3-(2,2,2-trifluoroethyl)-3H-pyrrolo(3,2-f)quinolin-7(6H)-one
Androgens
Receptors, Androgen