Antiplatelet effects of MK-852, a platelet fibrinogen receptor antagonist, in healthy volunteers.
MK-852, a cyclic heptapeptide, is a potent platelet fibrinogen receptor antagonist. When administered to normal healthy male subjects by 1- and 4-hour constant rate intravenous infusions, it provides a generally well-tolerated and reversible means of inhibition of platelet function. At infusion rates of 1 microgram/kg/min for 1 hour and 0.44 microgram/kg/min for 4 hours, respectively, MK-852 extended baseline bleeding time by greater than 2.2-fold and 2.6-fold, inhibited ADP-induced platelet aggregation by 76% and 69%, and inhibited collagen-induced platelet aggregation by 65% and 67%, respectively. The pharmacokinetics of MK-852 include an elimination half-life of approximately 2 hours, total clearance of about 150 ml/min, and volume of distribution of about 18 liters. Examination of the relationship between MK-852 whole-blood concentration in vitro and inhibition of platelet aggregation showed an EC50 of about 55 ng/ml and a Hill coefficient of 1.55. The infusions were generally well tolerated, with no study drug-related changes in blood counts or biochemical profiles.
Greenberg
H E
HE
Department of Medicine, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.
Wissel
P
P
Barrett
J
J
Barchowsky
A
A
Gould
R
R
Farrell
D
D
Panebianco
D
D
Hand
E
E
Gillen
L
L
Goldberg
M R
MR
Bjornsson
T D
TD
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000328:Adult; D019540:Area Under Curve; D003094:Collagen / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D009842:Oligopeptides / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D010979:Platelet Function Tests; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D053778:Thiazolidines; D013997:Time Factors
D009842:Oligopeptides; D010456:Peptides, Cyclic; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D053778:Thiazolidines; C083231:MK 0852; D000244:Adenosine Diphosphate; D003094:Collagen