BMS-214778 is a novel melatonin receptor agonist that may be a useful treatment for sleep disorders that result from disruption of circadian rhythms. Pharmacokinetic studies following intravenous and oral administration and 1 month oral steady-state studies were carried out in rats and monkeys. Rat brain was analyzed for BMS-214778 to determine the extent of its penetration from plasma. Equilibrium dialysis was employed to determine the extent of binding of [(14)C]-BMS-214778 to rat, monkey, and human sera proteins. In vitro metabolism studies with BMS-214778 in rat, monkey, and human liver homogenate preparations (S-9), with monkey and human liver slice preparations, and with pooled human liver microsomes were performed and the incubates analyzed for potential metabolites. Recombinant microsomes expressing specific human cytochrome P(450) (CYP) enzymes were employed to identify possible human metabolic pathways. BMS-214778 showed a high hepatic extraction and high degree of tissue distribution. BMS-214778 also displayed non-linear oral pharmacokinetics. Systemic exposures following oral doses in rats and monkeys increased more than proportionally to the increment in dose. Loss of systemic exposure to BMS-214778 upon chronic oral dosing was observed in male rats where exposure was one-half to two-thirds compared to a single dose, while modest decreases in exposure were observed upon chronic dosing in both sexes of monkey. This was suggestive of induction of BMS-214778 clearance and/or excretion mechanisms. BMS-214778 distributed from the plasma to brain in the rat (mean +/- SD brain:plasma ratio of 0.9 +/- 0.1, N = 3). [(14)C]-BMS-214778 was moderately bound to serum proteins (<91% bound) in all species examined. In vitro metabolism of BMS-214778 was mostly by hydroxylation and dehydrogenation, with CYP1A1, 1A2, 2D6, and 2C9 being the most likely isoforms to be involved in its metabolism in humans.