Abstract

The metabolic disposition of RS-26306, a new potent luteinizing hormone-releasing hormone antagonist, was studied in rats and monkeys after single i.v. and sc administration with the 3H-labeled compound. Plasma pharmacokinetics after iv administration were: CLs = 2.5 ml/min/kg, Vd beta = 0.29 liter/kg, t1/2 = 1.4 hr (rats), and CLs = 0.8 ml/min/kg, Vd beta = 0.32 liter/kg, t1/2 = 5.1 hr (monkeys). Cmax and Tmax in rats were 0.53 micrograms/ml and 4 hr after the 1 mg/kg sc dose, and were 1.07 micrograms/ml and 12 hr after the 10 mg/kg sc dose. AUC0-infinity after the 10 mg/kg sc dose in rats was seven times that after the 1 mg/kg sc dose. Apparent plasma disappearance t1/2 in rats were 3.6 and 15.2 hr, respectively, after the 1 and 10 mg/kg sc doses. An average of 12 and 4% of dose radioactivity remained at the injection site in rats 3 and 10 days, respectively, after a 10 mg/kg sc dose. In monkeys, Tmax after a 1 mg/kg sc dose was 0.5 hr for three animals but was 24 hr for the fourth animal, although plasma of this monkey contained substantial levels of RS-26306 between 15 min and 24 hr. Apparent plasma t1/2 in monkeys after a 1 mg/kg sc dose was at least 19 hr. Our data suggest depot formation after sc doses. In vitro plasma binding amounted to 82-84%. Excretion was mainly biliary: 12-25 and 55-84% of dose radioactivity was recovered in urine and feces, respectively, in both species. The biological samples contained only traces of 3H2O. Three metabolites, which were truncated peptides of the parent decapeptide, were identified in the rat bile. One of these was also present in the monkey plasma. The restricted enzymatic degradation of RS-26306, extensive plasma binding, and long circulating t1/2 of RS-26306 contribute to its prolonged activity in animal models and in humans.