Comparison of biological effects of a sustained delivery system and nonencapsulated LH-RH antagonist SB-75 in rats.
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 < 0.01) downregulation of membrane receptors for LH-RH 7 days after administration.(ABSTRACT TRUNCATED AT 250 WORDS)
Pinski
J
J
Endocrine, Polypeptide and Cancer Institute, VA Medical Center, New Orleans, LA 70146.
Yano
T
T
Groot
K
K
Milovanovic
S
S
Schally
A V
AV
D000818:Animals; D002214:Capsules; D003692:Delayed-Action Preparations; D015536:Down-Regulation / Q000187:drug effects; D005837:Genitalia, Male / Q000187:drug effects; D007987:Gonadotropin-Releasing Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000493:pharmacokinetics; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011966:Receptors, LHRH / Q000187:drug effects / Q000378:metabolism; D013739:Testosterone / Q000097:blood / Q000378:metabolism
D002214:Capsules; D003692:Delayed-Action Preparations; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; C062876:cetrorelix