Comparison of biological effects of a sustained delivery system and nonencapsulated LH-RH antagonist SB-75 in rats

Abstract Recently, we developed long-acting microcapsules and microgranules of the LH-RH antagonist SB-75. In this study, we compared the inhibitory effects of a single injection of encapsulated and nonencapsulated LH-RH antagonist SB-75 on gonadotropin and testosterone secretion. The resulting serum SB-75 levels were also measured by RIA. Microgranules containing 4% of this antagonist in poly( dl -lactide- co -glycolide) were administered IM at two different doses (30 and 60 mg/rat) to male rats. Other groups of rats were injected SC with equivalent doses of nonencapsulated SB-75 (1.25 and 2.5 mg/rat). The administration of microgranules at a dose of 60 mg/rat produced a significant elevation of serum SB-75 until day 76, and serum testosterone and LH levels were suppressed below the detection limit of the RIA for a period of 70 days. An equivalent dose of nonencapsulated SB-75 acetate (2.5 mg/rat) produced a significant elevation of SB-75 levels for 20 days and decreased testosterone to castration values and LH levels for merely 21 days. In rats treated with 30 mg microgranules of SB-75 or an equivalent dose of SB-75 acetate (1.25 mg/rat), serum testosterone and LH were suppressed to a similar extent, but for only 2 weeks. In another study, the effect of a single SC injection of 1.25 mg/rat of antagonist SB-75 on pituitary LH-RH receptors was determined, 7 and 60 days after administration. SB-75 produced a significant ( p ) downregulation of membrane receptors for LH-RH 7 days after administration. Our results indicate that the suppression of the pituitary-gonadal axis in rats effected by administration of microgranules of LH-RH antagonist SB-75 is more efficacious than that caused by an equivalent dose of unencapsulated SB-75 and suitable doses of microgranules can maintain elevated levels of SB-75 for several weeks.