DISPOSITION AND METABOLISM OF THE SULFONYLUREA ONCOLYTIC AGENT LY295501 IN MOUSE, RAT, AND MONKEY

The disposition and metabolism of LY295501 was studied in mice, rats, and monkeys, This novel diaryl sulfonylurea oncolytic agent is structu rally related to sulofenur and shows excellent activity in a broad ran ge of mouse antitumor models, The compound is well absorbed, giving pl asma concentrations greater than 200 mu g/ml after oral doses of 30-10 0 mg/kg, where it appears to be completely bound (>99.9%) to plasma pr oteins. The high degree of protein binding may be a factor in its rela tively long half-life, which ranges from about 8 hr in rats and 15 hr in mice to 50 hr in monkeys. While more material was excreted in feces than in urine from mice and rats given single oral doses of [C-14]LY2 95501, urine was the major route of elimination in monkeys. Three majo r metabolites - all formed via oxidation of the saturated part of the benzodihydrofuran moiety - were characterized in the urine of mice, ra ts, and monkeys. It is interesting that two of these metabolites are d erived from opening of this saturated ring, an unusual metabolic proce ss which represents a significant part of the metabolism of LY295501, As with sulofenur, metabolites of 3,4-dichloroaniline formed after met abolic cleavage of the sulfonylurea linkage were also found in urine, Unlike sulofenur, these do not seem to have major toxicological signif icance, but their formation does explain the minor methemoglobinemia o bserved in toxicology studies of LY295501, Even though only trace amou nts of LY295501 were found in urine, LY295501 is the predominant drug- related material in plasma, along with small amounts of other, relativ ely nonpolar, metabolites.