Sobolevsky Tim, Dikunets Marina, Sukhanova Irina, Virus Edward, Rodchenkov Grigory
Moscow Antidoping Centre, 105005, Moscow, Elizavetinsky per. 10, Russia.
Drug Test Anal. 2012 Oct;4(10):754-60. doi: 10.1002/dta.1413. Epub 2012 Sep 13.
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.
过氧化物酶体增殖物激活受体δ（PPARδ）激动剂是具有潜在提高运动成绩特性的候选药物，因此应控制其在体育界的非法使用。为模拟PPARδ激动剂GW0742的代谢过程，进行了体外反应，结果表明主要代谢途径是无环二价硫的氧化，生成相应的亚砜和砜。经液相色谱-质谱联用仪（LC-MS）鉴定后，在一项可控排泄研究后收集的尿液样本中对这些代谢物进行了评估。为作比较，还进行了GW1516的排泄研究。结果表明，GW1516和GW0742最好作为砜类代谢物进行监测，单次口服15毫克后，分别在40天和20天内，使用基于LC-MS/MS的方法可在尿液中检测到它们。未代谢的化合物仅在短时间内可测量，且浓度处于低纳克/毫升水平。GW1516和GW0742的亚砜与砜的比例在1:3至1:15范围内不规则变化，具体取决于给药后的时间，且有随时间增加的趋势。另一个重要发现是，GW0742及其代谢物在尿液中的丰度比GW1516的情况低约十倍。
