Disposition of 14C-LY195115 (1,3-dihydro-3,3-dimethyl-5-[1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl-6-14C]-2H-indol-2-one), a potent cardiotonic drug, in several animal species

Following the oral administration of 14C-LY195115 to rats, mice, dogs, and monkeys (25,15,5, and 5 mg/kg, respectively), between 40 and 60% of the radioactivity was excreted into the urine within 24 hr. The elimination half-time of radioactivity from plasma was approximately 5 hr for rats and mice, 8 hr for monkeys, and 14 hr in dogs. Analysis of the 24 hr urine by thin-layer chromatography (tlc) revealed that the predominant radioactive moiety from all species was parent drug (> 30% of the dose). The urinary metabolite profile in the monkey showed parent drug and 2 polar, minor metabolites. The pattern was similar in rats, mice and dogs. Additionally in monkeys there was a very polar metabolite which was not conjugated with β-glucuronic acid. The major metabolite in the urine was isolated and shown to have a molecular weight of 255 (LY195115=257). Synthesis of the dehydro derivative of LY195115 indicated that the metabolite was identical to this material. A tissue distribution study in rats, following an oral dose of 14C-LY195115 resulted in no apparent accumulation of radioactivity in any particular organ