PERSISTENT SUPPRESSION OF THE PITUITARY-GONADAL SYSTEM IN FEMALE RATSBY 3-MONTH DEPOT INJECTABLE MICROSPHERES OF LEUPRORELIN ACETATE

The serum drug levels and pharmacological effects of leuprorelin aceta te (leuprolide acetate) in female rats after subcutaneous (sc) injecti on of 3-month release injectable and biodegradable microspheres were i nvestigated. After sc injection, the microspheres provided sustained s erum drug levels for >3 months, probably because of continuous release of the drug. As was found for the 1-month depot preparation, a transi ent initial high peak in serum leuprorelin levels resulting from an in itial burst of drug release could not be avoided. Sustained suppressio n of serum luteinizing hormone (LH), follicle-stimulating hormone (FSH ), and estradiol for >16 weeks was attained by a single injection of t he microspheres. An injection of the microspheres suppressed the growt h of the ovaries and uterus in a dose-dependent manner, a drug dose of 0.036 mg (corresponding to similar to 1 mu g/kg/day) was insufficient for suppression of uterine growth, and a drug dose of 3.6 mg (corresp onding to similar to 100 mu g/kg/day) provided the strongest growth su ppression in both organs. Serum LH, FSH, and estradiol responses in a challenge test indicated that definite pharmacological effects were su stained for at least 16 weeks, as was demonstrated previously in male rats and dogs. Thus, this depot formulation may provide sustained ther apeutic effects for 3 or 4 months in humans.