Pharmacokinetics and pharmacodynamics of L-703,014, a potent fibrinogen receptor antagonist, after intravenous and oral administration in the dog.

Abstract

The pharmacokinetics and pharmacodynamics of L-703,014, a fibrinogen receptor antagonist, have been examined in the dog. An analytical method which utilizes methanol precipitation of dog plasma proteins followed by HPLC with an automated column switching technique using the chemical analogue L-704,326 as internal standard was developed for the determination of L-703,014 in dog plasma. The compound was not metabolized in the dog and was eliminated in the kidneys and into bile. Of the administered dose, 68.9 +/- 1.3% (i.v.) and 80.5 +/- 11.9% (p.o.) were recovered in the feces; 20.3 +/- 1.3% (i.v.) and 2.2 +/- 0.2% (p.o.) were recovered in the urine by 72 hr. L-703,014 was 23 +/- 3.4% bound in dog plasma protein and the mean ratio of plasma/whole blood was 1.22 +/- 0.05. The mean terminal half-life was 118 +/- 36 min, the mean steady-state volume of distribution was 0.61 +/- 0.22 L/kg, and the mean plasma clearance was 8 +/- 2 mL/min/kg. Ex vivo platelet aggregation measurements were made by inducing platelet aggregation with 10 micrograms/mL collagen in the presence of 1 microM epinephrine as an agonist. The mean C50 was 44.4 +/- 6.0 ng/mL, and the mean Hill coefficient was 1.5 +/- 0.3. The mean bioavailability was 4.9 +/- 1.4% in dogs administered 2.0 mg/kg (p.o.).