Detection of PPARδ agonists GW1516 and GW0742 and their metabolites in human urine

Abstract

Peroxisome proliferator-activated receptor-δ (PPARδ) agonists are the drug candidates with potential performance-enhancing properties, and therefore their illegitimate use in sports should be controlled. To simulate the metabolism of PPARδ agonist GW0742, in vitro reactions were performed which demonstrated that the main metabolic pathway is oxidation of the acyclic divalent sulfur to give the respective sulfoxide and sulfone. After being characterized by liquid chromatography-mass spectrometry (LC-MS), these metabolites were evaluated in urine samples collected after a controlled excretion study. For comparative purposes, GW1516 excretion study was also performed. It has been shown that GW1516 and GW0742 are best monitored as the sulfone metabolites which are detectable in urine using LC-MS/MS based procedure up to 40 and 20 days after a single oral dose of 15 mg each, respectively. The unmetabolized compounds are measurable only for a short period of time and at low ng/ml level. The sulfoxide-to-sulfone ratio for both GW1516 and GW0742 changed irregularly in the range of 1:3 to 1:15 depending on time elapsed after administration with a tendency of increasing the ratio with time. The other important finding was that the abundance of GW0742 and its metabolites in urine is about ten times lower than in case of GW1516.

Doping control analysis of GW1516 in equine plasma using liquid chromatography/electrospray ionization Q‐Exactive high‐resolution mass spectrometry

“…In contrast to the rodent toxicity studies, 1,9,10 no significant adverse effects were reported in clinical studies, probably due to the considerably lower dose administered (up to 10 mg/kg/day) and shorter administration period (up to 12 weeks) 1 . In our study, considering the possible risk of carcinogenicity of GW1516, only a single low oral dose of 0.3 mg/kg (150 mg/horse) was administered to a thoroughbred mare with reference to a healthy volunteer study in which a single oral dose of 15 mg was administered 7 …”

“…To control the misuse of GW1516 by human athletes, Thevis et al 5,6 reported the generation of two potential monitoring targets, namely GW1516 sulfoxide and sulfone (Figure 1), based on two in vitro studies. Sobolevsky et al later administered oral GW1516 to a healthy volunteer and confirmed the suitability and applicability of GW1516 sulfoxide and its sulfone for doping control 7 . For horses, only detection of GW1516 in hair was reported by Gray et al in 2018 15 .…”

Interconnection of sulfides and sulfoxides in medicinal chemistry

“…The ratio of 6 to 5 is at least 3:1 and increases with time. Consequently, 6 is a suitable marker to identify abuse of 4 …”

Emerging drugs affecting skeletal muscle function and mitochondrial biogenesis – Potential implications for sports drug testing programs

“…Mitochondrial biogenesis was not observed using 16 in the absence of any exercise stimulus; however, concomitant training of the test animals resulted in a 60–75% increase in their endurance performance exhibiting a specific “endurance gene signature” . Consequently, PPARβ/δ agonists have been considered as prohibited substances in sport since 2008, and test methods led to a series of adverse analytical findings for GW1516 in the past, despite the fact that the drug development was discontinued in 2007 due to observed increased risks of cancer in animal studies. Further substances that reportedly act as PPARβ/δ agonists are GW0742 and L165041 (Table , Fig.…”