Disposition of MK-852, a fibrinogen receptor antagonist, in rats and dogs.
MK-852, an antagonist of the platelet fibrinogen receptor GPIIb/IIIa, is the cyclic disulfide N-acetyl-cys-asn-(5,5-dimethyl-4-thiazolidine-carbonyl)- (4-aminomethyl-phe)-gly-asp-cys, monoacetate (all L-amino acids). Radiolabeled MK-852 was synthesized with either a 3H label in the N-acetyl group of the cystine residue or a 14C label in the aminomethyl group. Plasma concentrations of unchanged MK-852 in five rats declined with a mean terminal half-life of 0.92 hr after a 2.5 mg/kg i.v. dose of MK-852; plasma clearance and Vd were 23.1 ml/min/kg and 1.81 liters/kg, respectively. More label was excreted in urine (74-76%) than in feces (7-15%) when either [3H]MK-852 or [14C]MK-852 was given intravenously to groups of four rats (2.5 mg/kg). High concentrations of 3H in rat kidney were consistent with high renal clearance of MK-852, and MK-852 accounted for virtually all of the urinary 3H (and 14C) label. Following a 0.6 mg/kg i.v. dose, the half-life, plasma clearance, and Vd of MK-852 in four dogs were 0.84 hr, 3.93 ml/min/kg, and 0.28 liters/kg, respectively. In dogs, the excretion patterns of radioactivity were similar to those of rats, except that 14C urinary recoveries (79%) were higher than 3H (63%). Unchanged MK-852 represented essentially all of the urinary 3H label. Fractionation of dog 14C urinary radioactivity yielded one major and several minor polar labeled species. The major species was unchanged [14C]MK-852 (quantitated by radioimmunoassay as approximately 80% of the label).(ABSTRACT TRUNCATED AT 250 WORDS)
Vickers
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Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486.
Duncan
C A
CA
Yuan
A S
AS
Vyas
K P
KP
D000595:Amino Acid Sequence; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D008297:Male; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D010456:Peptides, Cyclic / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000032:analysis; D010975:Platelet Aggregation Inhibitors / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D053778:Thiazolidines; D014018:Tissue Distribution; D014316:Tritium
D001798:Blood Proteins; D002250:Carbon Radioisotopes; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D053778:Thiazolidines; D014316:Tritium; C083231:MK 0852; C090347:4-aminomethylphenylalanine; D010649:Phenylalanine