Disposition of the novel serotonin agonist, LY228729, in monkeys and rats

The disposition of a novel 5HT-1a agonist, LY228729, was studied in rats after oral administration and in monkeys after both i.v. and oral administration of a radiolabeled drug. Plasma concentrations of LY228729 declined with a half-life of 2.3 and 1.5 hr in monkeys after oral dosing and i.v. administration, respectively, and 1.9 hr in rats dosed orally. Peak plasma concentrations of the N-despropyl metabolite were greater than the parent drug following oral administration in both rats and monkeys and declined with a half-life of 3.2-3.5 hr. Plasma levels of total radioactivity rapidly exceeded that of the parent drug in both species. Radioactivity was eliminated more slowly, with terminal half-lives of 39.4 hr in the monkey and 48.6 hr in the rat. The parent drug and its despropyl metabolite accounted for only a small percentage of the total radioactivity in the plasma. Following i.v. and oral administration, radioactivity was eliminated predominantly in the urine of monkeys, but was distributed evenly between the urine and feces of rats. Parent drug and the N-despropyl metabolite were the major products in rat urine. In the monkey, the major metabolite was an uncharacterized polar compound.