PHARMACOKINETIC AND PHARMACODYNAMIC STUDIES OF A THROMBOXANE SYNTHETASE INHIBITOR, OZAGREL, IN RABBITS

The pharmacokinetic and pharmacodynamic (PK/PD) characteristics of oza grel, a new potent and selective thromboxane synthetase inhibitor, wer e investigated in rabbits after its intravenous, oral, and rectal admi nistration. Serum level of TXB(2) (the stable metabolite of TXA(2)), a direct pharmacological marker, was measured after each dosing. A mark ed reduction of serum TXB(2) within 30 min was shown after the three r outes of administration, reflecting rapid onset of action. Due to rapi d and complete absorption (i.e., T-max; 20 min, bioavailability; 100%) and longer duration of pharmacological action after rectal dosing, th e rectum offers a practical delivery route for ozagrel. An E(max) mode l was employed to fit the pharmacological data, and IC50 and E(max) fo r thrombosane synthetase inhibition were estimated to be 56.0 ng/ml an d 93%, respectively. These pharmacodynamic parameters were incorporate d into an integrated mathematical model to simulate the PK/PD profiles of ozagrel after i.v., oral, and rectal administration at lower (50 m g) and higher (200 mg) doses, and good agreement between the experimen tal and calculated values was achieved. The present PK/PD model may be useful for optimizing the therapeutic regimens of ozagrel.