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-o ver fashion, to conscious dogs or to dogs anesthetized with pentobarbi tal. Plasma concentrations of L-734217 were measured using a radioimmu noassay 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 we re significantly higher than those in the control animals. Correspondi ng to the increased plasma levels, the mean ex vivo inhibitory effects on ADP-or collagen-induced platelet aggregation in dogs under anesthe sia appeared greater than in those without the anesthetic treatment. P harmacokinetic analysis revealed a modest, but significant (up to 40%) elevation in the area under the plasma concentration-time curve durin g 6h of the drug administration, and a reduction in L-734217 plasma cl earance and volumes of distribution, in the anesthetized dogs. Analysi s of pharmacodynamic data indicated that the EC50 and the Hill coeffic ient of the platelet aggregation response-plasma concentration curve w ere not altered by pentobarbital treatment. The results are in agreeme nt with the findings that the administration of pentobarbital alone (i n the absence of L-734217) did not affect appreciably the ex vivo plat elet 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 no t bind substantially to canine plasma proteins or blood cellular compo nents. It is possible that alterations of regional hemodynamics, repor tedly mediated by pentobarbital, contributed to changes observed in th e present study. That is, alterations occurred in L-734217 elimination ;and distribution processes which resulted in an increase in drug plas ma levels. Since pentobarbital anesthesia infuenced only the pharmacok inetics, and not the pharmacodynamics, of L-734217, the apparent incre ases in the inhibition of platelet aggregation responses observed foll owing L-734217 administration to the anesthetized dogs were probably s equential effects of the pharmacokinetic interactions. (C) 1997 John W iley & Sons, Ltd.