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)