title: Variation in the ability of glycoprotein IIb-IIIa antagonists to exert and maintain their inhibitory effects on the binding of fibrinogen.
abstract: Tirofiban and eptifibatide dissociate rapidly from glycoprotein IIb-IIIa but have different dissociation constants (KD of tirofiban = 15 nmol/L, that of eptifibatide = 120 nmol/L). Binding of fibrinogen to glycoprotein IIb-IIIa is biphasic, forming an initial reversible complex (KD = 155-180 nmol/L) and a second more stable complex (KD = 20-70 nmol/L). To test whether a comparable extent of inhibition would be maintained by pharmacologic antagonists that exhibit a rapid rate of release, blood from 26 patients with symptomatic coronary artery disease was added to reaction tubes containing a concentration of either agent that had been shown to achieve optimal inhibition (for tirofiban 100 ng/mL, for eptifibatide 1.7 microg/mL) plus a platelet agonist (1 microM adenosine diphosphate [ADP] or 25 microM thrombin receptor agonist peptide [TRAP]), and fluorochrome labeled fibrinogen before analysis by flow cytometry. The extent of inhibition early on (30 seconds to 3 minutes) was similar. By contrast, the extent of inhibition 10 to 15 minutes later was maintained more effectively with tirofiban than eptifibatide (difference in slope P < 0.01). The differences are consistent with the biphasic binding of fibrinogen to GP IIb-IIIa. The clinical implications of this observation merit evaluation to potentially improve care of patients and to guide future drug development.
authors.affiliation: Cardiology Unit, Department of Medicine, University of Vermont, Burlington, Vermont 05446, USA. david.schneider@uvm.edu
authors.forename: David J
authors.initials: DJ
authors.lastname: Schneider
authors.forename: Patricia Q
authors.initials: PQ
authors.lastname: Baumann
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Whitaker
authors.forename: Burton E
authors.initials: BE
authors.lastname: Sobel
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000368:Aged; D001667:Binding, Competitive / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D000077144:Clopidogrel; D003324:Coronary Artery Disease / Q000175:diagnosis / Q000378:metabolism / Q000503:physiopathology; D003627:Data Interpretation, Statistical; D000077542:Eptifibatide; D005340:Fibrinogen / Q000378:metabolism*; D005434:Flow Cytometry / Q000379:methods; D016650:Fluorescein-5-isothiocyanate; D006801:Humans; D007457:Iodine Radioisotopes; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000378:metabolism / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018179:Receptors, Thrombin / Q000819:agonists / Q000378:metabolism; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000077466:Tirofiban; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology
chemical_list: D007457:Iodine Radioisotopes; D010446:Peptide Fragments; D010455:Peptides; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D018179:Receptors, Thrombin; C086309:thrombin receptor peptide SFLLRNP; D014443:Tyrosine; D000244:Adenosine Diphosphate; D005340:Fibrinogen; D000077144:Clopidogrel; D000077466:Tirofiban; D016650:Fluorescein-5-isothiocyanate; D000077542:Eptifibatide; D013988:Ticlopidine