Pharmacokinetic and Pharmacodynamic Studies of a Thromboxane Synthetase Inhibitor, Ozagrel, in Rabbits

The pharmacokinetic and pharmacodynamic (PK/PD) characteristics of ozagrel, a new potent and selective thromboxane synthetase inhibitor, were investigated in rabbits after its intravenous, oral, and rectal administration. Serum level of TXB2 (the stable metabolite of TXA2), a direct pharmacological marker, was measured after each dosing. A marked reduction of serum TXB2 within 30 min was shown after the three routes of administration, reflecting rapid onset of action. Due to rapid and complete absorption (i.e., Tmax ; 20 min, bioavailability ; 100%) and longer duration of pharmacological action after rectal dosing, the rectum offers a practical delivery route for ozagrel. An Emax model was employed to fit the pharmacological data, and IC50 and Emax for thromboxane synthetase inhibition were estimated to be 56.0 ng/ml and 94%, respectively. These pharmacodynamic parameters were incorporated into an integrated mathematical model to simulate the PK/PD profiles of ozagrel after i.v., oral, and rectal administration at lower (50 mg) and higher (200 mg) doses, and good agreement between the experimental and calculated values was achieved. The present PK/PD model may be useful for optimizing the therapeutic regimens of ozagrel.