RT Journal Article
SR Electronic
T1 Disposition and metabolism of the Sulfonylurea Oncolytic Agent LY295501 in Mouse, Rat, and Monkey
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 701
OP 708
VO 25
IS 6
A1 William J. Ehlhardt
A1 Joseph M. Woodland
A1 John E. Toth
A1 James E. Ray
A1 Diana L. Martin
YR 1997
UL http://dmd.aspetjournals.org/content/25/6/701.abstract
AB 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 μg/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 formedvia 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. The American Society for Pharmacology and Experimental Therapeutics