Metabolism and disposition of the anticancer agent sulofenur in mouse, rat, monkey, and human.
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)
Department of Drug Metabolism, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285.
W J
WJ
Ehlhardt
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D001646:Bile / Q000378:metabolism; D005260:Female; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D051381:Rats; D011916:Rats, Inbred F344; D013045:Species Specificity; D013453:Sulfonylurea Compounds / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine
D000970:Antineoplastic Agents; D013453:Sulfonylurea Compounds; C058179:sulofenur