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Published on: November 24, 2014
Disposition and metabolism of the sulfonylurea oncolytic agent LY295501 in mouse, rat, and monkey
W J Ehlhardt1, J M Woodland, J E Toth
1Lilly Research Laboratories, Indianapolis, IN 46285, USA.
Abstract:
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.
Insights
The novel oncolytic agent LY295501 is well absorbed and extensively protein-bound, with metabolism primarily occurring via oxidation in mice, rats, and monkeys. Elimination routes vary by species, with urine being major in monkeys.
Area of Science:
- Pharmacology
- Oncology
- Drug Metabolism
Background:
- LY295501 is a novel diaryl sulfonylurea oncolytic agent with antitumor activity.
- It is structurally related to sulofenur.
Purpose of the Study:
- To investigate the disposition and metabolism of LY295501 in preclinical species.
- To characterize the metabolic pathways and excretion routes of LY295501.
Main Methods:
- Administration of radiolabeled [14C]LY295501 orally to mice, rats, and monkeys.
- Analysis of plasma, urine, and feces for drug and metabolite concentrations.
- Characterization of metabolites using analytical techniques.
Main Results:
- LY295501 is well absorbed and highly protein-bound (>99.9%) with species-dependent half-lives (8-50 hr).
- Excretion predominantly via feces in rodents and urine in monkeys.
- Three major oxidative metabolites of the benzodihydrofuran moiety were identified, including ring-opened products.
- 3,4-dichloroaniline metabolites were formed but lacked toxicological significance, explaining minor methemoglobinemia.
Conclusions:
- LY295501 undergoes extensive metabolism, primarily through oxidation, with significant ring-opening of the benzodihydrofuran moiety.
- Species-specific differences in excretion routes and half-lives were observed.
- Metabolites of LY295501 are generally not toxicologically significant, despite minor methemoglobinemia observed.
