Phase I Study of Y‐20811, a New Long‐Acting Thromboxane Synthetase Inhibitor by Intravenous Administration

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Abstract
The safety, pharmacological action and pharmacokinetics of Y‐20811, a thromboxane (TX) synthetase inhibitor, were investigated by single intravenous administration of 5, 10, and 25 mg each to six healthy adult male volunteers. Throughout the entire test period, no abnormality attributable to the test drug was found in subjective and objective symptoms, routine laboratory tests, physical tests, or bleeding time; and the drug was well tolerated by subjects. Inhibition of serum TXB2 production and an increase in 6‐keto‐prostaglandin (PG) F1α production during whole‐blood coagulation exhibited a dose‐dependent change from 0.5 hours after administration. In addition, arachidonic acid (AA)‐induced platelet aggregation was inhibited, and adenosine diphosphate (ADP)‐induced secondary aggregation was also inhibited. The duration of these actions was long: inhibition of serum TXB2 production and the increase in 6‐keto‐PGF1α production lasted for 168 hours after administration, and inhibition of platelet aggregation lasted for more than 48 h after administration. The initial phase half‐life (t1/2α) and final phase half‐life (t1/2β) of Y‐20811, calculated from the change in plasma concentration, were 0.1–0.3 hours and 1.9–3.1 hours, respectively. The area under the plasma concentration‐time curve (AUC) increased in a dose‐dependent manner, but the values of volume of distribution (Vss) and total clearance (CLt) were almost constant in any dose group. At each of the three doses, 60–64% of the dose was excreted in unchanged form, and 8–10% in conjugated form in the urine, within 48 hours after administration. We concluded that the intravenous administration of Y‐20811 was very safe and inhibited TXB2 production and platelet aggregation.