The pharmacokinetics and pharmacodynamics of a new oral thromboxane (TX) A2 receptor antagonist, Z-335, were studied in healthy male volunteers following single doses (0.5-40 mg, PO) in a dose-escalating manner and multiple doses (40 mg, PO, once daily for 7 consecutive days) with a single-blind, placebo-controlled design. Serial blood and urine samples were analyzed for Z-335 and its metabolites to obtain key pharmacokinetic parameters. In the single-dose (10, 20, and 40 mg) study, the maximum plasma concentration (Cmax) and area under the plasma concentration versus time curve (AUC) increased in proportion to the dose when administered afterfasting, while the mean elimination half-life (t1/2beta) was essentially unchanged (7.79-7.93 h). Recovery of the unchanged and taurine-conjugated drugs in the urine within 24 hours was 6.5% to 8.4% and 11.9% to 14.2%, respectively. These parameters essentially remained unchanged when the effect of meal intake was evaluated at the dose of 20 mg with a crossover design. Ex vivo platelet aggregation in the plasma by a TXA2 analogue, U46619, was completely inhibited within 2 hours after all doses, and complete inhibition was maintained for 12 to 14 hours, depending on the dose. The aggregation induced by collagen was also inhibited to a lesser extent, whereas that by adenosine diphosphate was hardly influenced. In the multiple-dose study, Cmax and AUC0-24 were increased by 34% after the last dose compared with the first dose. Z-335 afforded extensive inhibition of platelet aggregation by U46619 throughout the administration period, which returned, however, almost to the control level 48 hours after the last dose. The agent was well tolerated without any abnormalities in subjective and objective symptoms, blood biochemistry, hematology, and urinalysis definitely attributable to the agent, except for the changes expected from its TXA2 receptor-antagonizing actions. Z-335 was concluded to be safe and to provide long-lasting blockade of TXA2 receptors on the basis of a once-daily regimen, promoting further clinical evaluation.