SPECIES VARIATION IN THE EFFECT OF GLYCOPROTEIN-IIB IIIA ANTAGONISTS ON INHIBITION OF PLATELET-AGGREGATION/

Differences exist between platelets of different species in their reac tion to pharmaceutical agents, such as inhibitors of platelet aggregat ion. Understanding these differences is critical in the interpretation of data from experimental animal models of thrombosis. Platelet aggre gation, essential in the hemostatic process, requires that fibrinogen (fgn) bind to activated platelets. Analogs of Arginine-Glycine-Asparti c acid-Phenylalanine (RGDF), a peptide sequence of fgn, block fgn bind ing to its receptor known as glycoprotein (GP) IIb/IIIa on activated p latelets and prevent aggregation. We studied the inhibition resulting from Arginine-Glycine-Aspartic acid-Serine (RGDS) and two analogs of R GDF, (SC-46749 and SC-47643) on aggregation of human, rat, guinea pig, dog, and rhesus monkey platelets in vitro using ADP as the agonist. T he inhibitory potency of RGDS, SC-46749, ad SC-47643 was species depen dent. The rank order of potency was rhesus monkey, dogs, and human fol lowed by guinea pig and rat. In order to study the relative inactivity of the compounds in rat platelets compared to human, we diluted rat p latelet-rich plasma (PRP) to yield platelet levels approximating that of humans. Platelet inhibition was not significantly changed in dilute d rat PRP nor did changing concentration appear to affect activity in human PRP. Our data suggest that the platelet response of some species may better represent human response with regard to inhibition of GP I Ib/IIIa by (RGDX) analogs.