The disposition and metabolism of
LY295501 was studied in mice, rats, and monkeys. This novel diaryl sulfonylurea oncolytic agent is structurally related to
sulofenur and shows excellent activity in a broad range of mouse antitumor models. The compound is well absorbed, giving plasma concentrations greater than 200 micrograms/ml after oral doses of 30-100 mg/kg, where it appears to be completely bound (> 99.9%) to
plasma proteins. The high degree of protein binding may be
a factor in its relatively 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 [14C]
LY295501, urine was the major route of elimination in monkeys. Three major metabolites-all formed via oxidation of the saturated part of the benzodihydrofuran moiety-were characterized in the urine of mice, rats, and monkeys. It is interesting that two of these metabolites are derived from opening of this saturated ring, an unusual metabolic process which represents a significant part of the metabolism of
LY295501. As with
sulofenur, metabolites of
3,4-dichloroaniline formed after metabolic cleavage of the sulfonylurea linkage were also found in urine. Unlike
sulofenur, these do not seem to have major toxicological significance, but their formation does explain the minor
methemoglobinemia observed in toxicology studies of
LY295501. Even though only trace amounts of
LY295501 were found in urine,
LY295501 is the predominant
drug-related material in plasma, along with small amounts of other, relatively nonpolar, metabolites.