71236-01-6Relevant academic research and scientific papers
Synthesis, metabolism, and disposition of the antiinflammatory 3-[2-(4-methylphenyl)-thioethyl]-syndone-5-14C in the rat
Pirl,Bell,Lu,Bauer
, p. 578 - 584 (2007/10/02)
The synthesis, as well as the in vivo and in vitro disposition, of 3-[2-(4-methylphenyl)-thioethyl]-syndone-5-14C (5) in the rat is described. After intraperitoneal injection of a single dose of 5 in female Sprague-Dawley rats, the distribution and excretion of radioactive substances were monitored (24 h). Radioactivity in the blood declined in a biphasic manner with half-lives of 0.55 and 15.2 h for the α- and β-phase, respectively. About 8% of the administered radioactivity was detected in feces and approximately 90% in urine (24 h). In 3.75 h, 50% of the radio-dose was excreted in the urine. Tissue distribution studies demonstrated a selective uptake of radioactivity only by the adrenal glands and the ovaries. The radioactivity in these organs reached a maximum approximately 1 h after dosing and then declined rapidly. None of the parent drug was excreted from such a single dose (i.p. injection) which indicated rapid in vivo metabolism. Nor could there be found any metabolites related to the whole structure, for example, the sulfoxide or aromatic hydroxy compounds. The syndone 5, its sulfoxide and unconjugated metabolites were detected and quantitated by GC/MS methodology using unlabelled authentic samples. Radioactive carbon dioxide was not detected during the in vivo or in vitro experiments, nor was it released from alkaline urine samples upon acidification. Radiolabelled urinary metabolites were glycolic acid-1-14C (34%), its glycine conjugate 10 (52%) and 3-vinylsyndone-5-14C (4%). Unlabelled urinary metabolites were 4-methylthiophenol (4%) and 2-(4-methylphenylthio)-ethanol 13 (3%). The acid-labile conjugate of 13 (5%) was the only identifiable fecal metabolite. It is postulated that 5 is hydrolyzed enzymatically in the rat to the N-nitrosamino acid which would be expected to metabolize like a typical nitrosamine to yield 10 and 13. One of the ways 3-vinylsydnone and 4-methylthiophenol could arise is from an enzyme-mediated retro-Michael reaction of 5. In vitro studies of 5 were carried out with whole rat liver homogenates, their 20,000 x g supernatant, and blood and kidney homogenates. It was observed that water-soluble radioactive metabolites were produced relatively fast and were formed fastest in blood. At a concentration of 0.4 mg of sydnone per g tissue, blood metabolized 5 at a rate of 0.04 mg/g tissue per h.
