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Metabolism and disposition of the anticancer agent sulofenur in mouse, rat, monkey, and human
1Department of Drug Metabolism, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285.
Abstract:
The elimination and metabolism of sulofenur [N-(5-indanesulfonyl)-N'-(4-chlorophenyl)urea, LY186641] was examined in mice, rats, monkeys, and humans. The compound, which is efficacious in a wide number of solid-tumor in vivo models, is currently being developed as an anticancer agent. Its diarylsulfonylurea structure is unique among such agents, and the basis of its activity is unknown but apparently novel. A major goal of these studies was to determine whether p-chloroaniline is formed in significant quantities during the course of sulofenur metabolism. p-Chloroaniline, capable of being formed by hydrolysis of this diarylsulfonylurea, is known to induce methemoglobinemia and/or hemolytic anemia. In animal studies using rats and monkeys, as well as in clinical trials of sulofenur, elevated levels of methemoglobin have been noted. The metabolism was thus compared to the known metabolism of p-chloroaniline. Sulofenur (I) is well absorbed in both monkey and human; practically all of the excreted radiolabel from an oral dose is in the urine. Metabolism is extensive; the major excretion products are the 1-hydroxyindanyl (II) and 1-ketoindanyl (III) derivatives in all species, along with significant amounts of the 3-hydroxyindanyl (IV) and 3-ketoindanyl (V) metabolites in the mouse and rat. Dihydroxyindanyl secondary metabolites also are present, but no sulofenur is observed in the urine samples. Known metabolites account for over 95% of the radiocarbon present in urine samples from a patient given [14C-p-chlorophenyl]sulofenur.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Sulofenur, an anticancer drug, undergoes extensive metabolism in humans and animals. Key metabolites identified are indanyl derivatives, with no significant formation of p-chloroaniline observed.
Area of Science:
- Pharmacology and Toxicology
- Drug Metabolism and Pharmacokinetics
- Oncology
Background:
- Sulofenur is an investigational anticancer agent with a unique diarylsulfonylurea structure.
- Its efficacy in solid-tumor models suggests a novel mechanism of action.
- Concerns exist regarding potential formation of p-chloroaniline, a known inducer of methemoglobinemia, during sulofenur metabolism.
Purpose of the Study:
- To investigate the elimination and metabolism of sulofenur in preclinical species (mice, rats, monkeys) and humans.
- To determine if significant quantities of p-chloroaniline are produced during sulofenur metabolism.
- To compare sulofenur metabolism with the known metabolism of p-chloroaniline.
Main Methods:
- Administration of radiolabeled sulofenur to mice, rats, monkeys, and human subjects.
- Analysis of urine samples to identify and quantify metabolites.
- Comparison of metabolic profiles across species and with known p-chloroaniline metabolism.
Main Results:
- Sulofenur is well absorbed and extensively metabolized, with the majority of the dose excreted in urine.
- Major urinary metabolites identified across all species include 1-hydroxyindanyl and 1-ketoindanyl derivatives.
- Significant amounts of 3-hydroxyindanyl and 3-ketoindanyl metabolites were found in rodents; no sulofenur was detected in urine.
- Over 95% of radiocarbon in human urine was accounted for by known metabolites, with no evidence of significant p-chloroaniline formation.
Conclusions:
- Sulofenur metabolism is extensive and species-dependent, primarily yielding indanyl derivatives.
- The metabolism of sulofenur does not appear to generate significant amounts of p-chloroaniline.
- These findings are crucial for understanding the safety profile of sulofenur as an anticancer therapeutic.