Effects of pentobarbital on pharmacokinetics and pharmacodynamics of a potent fibrinogen receptor antagonist, L-734217, in dogs

Effects of pentobarbital on pharmacokinetics and pharmacodynamics of L-734217, a potent fibrinogen receptor antagonist, were studied in male dogs. L-734217 was given intravenously at 0.01 mgkg(-1), in a cross-over fashion, to conscious dogs or to dogs anesthetized with pentobarbital. Plasma concentrations of L-734217 were measured using a radioimmunoassay and inhibitory effects on ex vivo platelet aggregation induced by ADP or collagen were determined. In pentobarbital-treated dogs, L-734217 plasma concentrations during the first 3 h collection period were significantly higher than those in the control animals. Corresponding to the increased plasma levels, the mean ex vivo inhibitory effects on ADP-or collagen-induced platelet aggregation in dogs under anesthesia appeared greater than in those without the anesthetic treatment. Pharmacokinetic analysis revealed a modest, but significant (up to 40%) elevation in the area under the plasma concentration-time curve during 6h of the drug administration, and a reduction in L-734217 plasma clearance and volumes of distribution, in the anesthetized dogs. Analysis of pharmacodynamic data indicated that the EC50 and the Hill coefficient of the platelet aggregation response-plasma concentration curve were not altered by pentobarbital treatment. The results are in agreement with the findings that the administration of pentobarbital alone (in the absence of L-734217) did not affect appreciably the ex vivo platelet aggregatory responses. In a separate group of dogs, L-734217 was found to be metabolically stable, and was eliminated unchanged renally (64 +/- 4%) and hepatically (32 +/- 6%). In addition, L-734217 did not bind substantially to canine plasma proteins or blood cellular components. It is possible that alterations of regional hemodynamics, reportedly mediated by pentobarbital, contributed to changes observed in the present study. That is, alterations occurred in L-734217 elimination;and distribution processes which resulted in an increase in drug plasma levels. Since pentobarbital anesthesia infuenced only the pharmacokinetics, and not the pharmacodynamics, of L-734217, the apparent increases in the inhibition of platelet aggregation responses observed following L-734217 administration to the anesthetized dogs were probably sequential effects of the pharmacokinetic interactions. (C) 1997 John Wiley & Sons, Ltd.