Synthesis, metabolism, and disposition of the antiinflammatory 3-[2-(4-methylphenyl)-thioethyl]-sydnone-5-14C in the rat.

The synthesis, as well as the in vivo and in vitro disposition, of 3-[2-(4-methylphenyl)thioethyl]-sydnone-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 was monitored (24 h). Radioactivity in the blood declined in a biphasic manner with half-lives of 0.55 and 15.2 h for the alpha- and beta-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 sydnone 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 9 (34%), its glycine conjugate 10 (52%) and 3-vinylsydnone-5-14C 11 (4%).(ABSTRACT TRUNCATED AT 250 WORDS)