Effects of pentobarbital on pharmacokinetics and pharmacodynamics of a potent fibrinogen receptor antagonist, L-734 217, in dogs
✍ Scribed by T. Prueksaritanont; M. T. Stranieri; E. L. Hand; J. D. Ellis; M. A. Holahan; G. R. Sitko; J. J. Cook
- Publisher
- John Wiley and Sons
- Year
- 1997
- Tongue
- English
- Weight
- 364 KB
- Volume
- 18
- Category
- Article
- ISSN
- 0142-2782
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✦ Synopsis
Eects of pentobarbital on pharmacokinetics and pharmacodynamics of L-734 217, a potent ®brinogen receptor antagonist, were studied in male dogs. L-734 217 was given intravenously at 0´01 mg kg 71 , in a cross-over fashion, to conscious dogs or to dogs anesthetized with pentobarbital. Plasma concentrations of L-734 217 were measured using a radioimmunoassay and inhibitory eects on ex vivo platelet aggregation induced by ADP or collagen were determined. In pentobarbital-treated dogs, L-734 217 plasma concentrations during the ®rst 3 h collection period were signi®cantly higher than those in the control animals. Corresponding to the increased plasma levels, the mean ex vivo inhibitory eects 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 signi®cant (up to 40%) elevation in the area under the plasma concentration±time curve during 6 h of the drug administration, and a reduction in L-734 217 plasma clearance and volumes of distribution, in the anesthetized dogs. Analysis of pharmacodynamic data indicated that the EC 50 and the Hill coecient of the platelet aggregation response±plasma concentration curve were not altered by pentobarbital treatment. The results are in agreement with the ®ndings that the administration of pentobarbital alone (in the absence of L-734 217) did not aect appreciably the ex vivo platelet aggregatory responses. In a separate group of dogs, L-734 217 was found to be metabolically stable, and was eliminated unchanged renally (64+4%) and hepatically (32+6%). In addition, L-734 217 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-734 217 elimination and distribution processes which resulted in an increase in drug plasma levels. Since pentobarbital anesthesia in¯uenced only the pharmacokinetics, and not the pharmacodynamics, of L-734 217, the apparent increases in the inhibition of platelet aggregation responses observed following L-