Inhibitory effects of the potent antagonist of luteinizing hormone-releasing hormone N-Ac-[3-(2-naphthyl)-D-alanine1,4-chloro-D- phenylalanine2,3-(3-pyridyl)-D-alanine3,D-citrulline6, D-alanine10] luteinizing hormone-releasing hormone (SB-75) free of edematogenic effects were investigated in male rats. In a study to determine the effect on luteinizing hormone levels in castrated male rats, SB-75 was injected s.c. in doses of 0.625, 1.25, 2.5, 5.0, and 10 μg. Blood samples were taken at different intervals for 48 hr. All doses of SB-75 significantly decreased luteinizing hormone levels for >6 hr (P < 0.01); this inhibition lasted for >24 hr (P < 0.01) with a dose of 5.0 μg and >48 hr with 10 μg(P < 0.05). Serum testosterone levels were also measured in intact male rats injected with SB-75 in doses of 25, 50, and 100 μg. All doses produced a dramatic fall in testosterone to castration levels 6 hr after injection (P < 0.01); this inhibition of serum testosterone was maintained for >72 hr, but only the 100-μg dose could keep testosterone in the castration range for >24 hr (P < 0.01). In another study using a specific RIA, we obtained the pharmacokinetic release pattern of SB-75 from two sustained delivery formulations of SB-75 pamoate microgranules and examined their effect on serum testosterone. After a single i.m. injection of 20 mg of one batch of microgranules, a large peak corresponding to SB-75 at 45.8 ng/ml was observed, corresponding to the 'burst' effect. Levels of the analog decreased to 19.6 ng/ml on day 2, gradually reached a concentration of 4.7 ng/ml on day 7, and kept declining thereafter. Testosterone levels were reduced on day 1 (P < 0.01) and were maintained at low values for >7 days (P < 0.05). In rats injected with 10 mg of SB-75 pamoate microgranules of the second batch, SB-75 serum levels rose to 33 ng/ml 3 hr after administration and then fell gradually to ≃3.4 ng/ml on day 16, but a second small peak was seen on day 28. Subsequently, the analog levels decreased slowly to 2.9 ng/ml on day 42. At this time, testosterone serum levels were still significantly lower than in controls. These overall results demonstrate the efficacy of SB-75 in the suppression of the pituitary-gonadal axis. This modern luteinizing hormone-releasing hormone antagonist can possibly be used for treating sex hormone-sensitive cancers and other disorders.
