Pharmacokinetics of a novel butylated hydroxytoluene-thiazolidinone CNS antiischemic agent LY256548 in rats, mice, dogs, and monkeys

Mice, rats, dogs, and monkeys were given a single 50 mg/kg oral dose of [14C]LY256548. Plasma levels of radioactivity and LY256548 were determined, as was the excretion of radioactivity. Peak plasma levels of LY256548 occurred prior to those of radioactivity in mice, dogs, and monkeys, but were coincident in rats. The Cmax of LY256548 in rats, mice, dogs, and monkeys was 0.17, 0.30, 0.04, and 0.02 microgram/ml, respectively. However, the Cmax of radioactivity was 10-fold greater than that of LY256548 in rats and mice, 24-fold greater in dogs, and 40-fold greater in monkeys. The half-lives of LY256548 were substantially less than those of radioactivity in all four species. The oral absorption of LY256548 in rats, dogs, and monkeys was 45%, 7%, and 12%, respectively. The systemic bioavailability of LY256548 in rats, dogs, and monkeys was 6%, 0.4%, and 3%, respectively. Extensive biotransformation of LY256548 was observed in all four species. Fecal excretion of radioactivity was the primary mode of elimination, being 95% in rats, 81% in mice, 100% in dogs, and 68% in monkeys.