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 olidine-carbonyl)-(4-aminomethyl-phe)-gly-asp- cys, monoacetate (all L-amino acids). Radiolabeled MK-852 was synthesi zed with either a H-3 label in the N-acetyl group of the cystine resid ue or a C-14 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 iv dose of MK-852; plasma clearance and V -d were 23.1 ml/min/kg and 1.81 liters/kg, respectively. More label wa s excreted in urine (74-76%) than in feces (7-15%) when either [H-3]MK -852 or [C-14]MK-852 was given intravenously to groups of four rats (2 .5 mg/ kg). High concentrations of H-3 in rat kidney were consistent w ith high renal clearance of MK-852, and MK-852 accounted for virtually all of the urinary 3H (and C-14) label. Following a 0.6 mg/kg iv dose , the half-life, plasma clearance, and V-d of MK-852 in four dogs were 0.84 hr, 3.93 ml/min/kg, and 0.28 liters/kg, respectively. in dogs, t he excretion patterns of radioactivity were similar to those of rats, except that C-14 urinary recoveries (79%) were higher than H-3 (63%). Unchanged MK-852 represented essentially all of the urinary H-3 label. Fractionation of dog C-14 urinary radioactivity yielded one major and several minor polar labeled species. The major species was unchanged [C-14]MK-852 (quantitated by radioimmunoassay as similar to 80% of the label). One of the minor species was identified as p-amino-methylphen ylalanine accounting for similar to 5% of the urinary label. Plasma H- 3 radioactivity in both rats and dogs was associated with unchanged MK -852 and a volatile component (apparently (H2O)-H-3) that persisted in plasma without appreciable renal elimination. Because of the loss of the H-3 label, it was presumed that MK-852 underwent deacetylation. Ho wever, N-desacetyl MK-852 was not detected in urine.