The pharmacokinetics, plasma protein binding and metabolism of nipradilol (K-351: NIP), a new potent antihypertensive and antianginal agent, were compared in dogs, monkeys, rabbits and rats. In all species studied, NIP did not appreciably bind plasma protein (less than 30%) and was extensively distributed in tissues. There was a good correlation between the volume of distribution at steady state (Vss, 1) and body weight (B, kg) of the animal species as follows: Vss = 4.42 B0.805. In addition, Vss increased as a function of the plasma free fraction. Intrinsic clearance of unbound drug (CLuint, 1/h) also correlated with body weight as follows: CLuint = 4.78 B0.722, but blood clearance in rabbits exceeded hepatic blood flow, suggesting extrahepatic metabolism. Following oral administration, the systemic availability for all species increased with the oral dose, while the half-life was about 2 h, and was independent of dose. The apparent threshold dose (ATD, mg/kg) was observed to vary inversely with body weight of the animal species as follows: ATD = 4.33 B-0.472. Less than 2% of the dose was excreted into the urine as unchanged NIP in all species. The metabolic profile for all species was similar, but pronounced quantitative differences among species was observed for aliphatic and aromatic hydroxylation of the 3,4-dihydro-2 H-1-benzopyran ring.