Pharmacokinetic Characteristics of the Gonadotropin-Releasing Hormone Analog D-Ser(TBU)-6EA-10Luteinizing Hormone-Releasing Hormone (Buserelin) after Subcutaneous and Intranasal Administration in Children with Central Precocious Puberty

Abstract

A double antibody RIA was developed for the measurement of thelong-acting GnRH agonist DSer(TBU)⁶EA¹⁰GnRH (buserelin). The antibody, raised in rabbits against a buserelin-hemocyanin conjugate, reacted with the intact molecule and also molecular fragments containing the C_6-9 tetrapeptide sequence and permitted the measurement of buserelin activity in serum andurine. Natural GnRH, LH, and FSH did not cross-react in this assay system. The assay was applied to samples obtained from children receiving buserelinfor the management of central precocious puberty either by once daily injection of 30 ¼g/kg or by nasal spray (in; 200 μg every 8 h). Urine and serum samples, chromatographed on Sephadex G-25, contained immunoreactive material corresponding closely in molecular size to [¹²⁵I]buserelin. In unextracted serum samples taken at intervals after sc therapy in 11 girls, the peak immunoreactive buserelin levels of 52.2 α 14.8 ng/ml (mean α SEM) occurred at 30 min. The half-time of elimination was 74.9 α 36.9 min. Approximately 30% of the dose was detected in urine collected for 3 h after injection. Similar data were obtained in 3 normal adults given 10 μg/kg buserelin, iv. By contrast, after the administration of 200 /ig buserelin by metered nasal spray, the mean peak serum concentration in 10 girls was 100-fold less (0.65 α 0.14 ng/ml), although the halftime of elimination was almost identical. Only 0.73% of the nasal dose was excreted by 3 h. Calculated relative bioavailability data indicated maximal nasal absorption of 6%. However, absorption after nasal administration varied greatly, and in 2 children, serum and urinary concentrations of buserelin after supervised administration were negligible. We conclude that in buserelin therapy, in the dose used in this study, doesnot represent optimal treatment for the initial management of patients withprecocious puberty. The success of in therapy in sustaining initial effectsof buserelin given by sc administration presumably reflects changes in receptor sensitivity induced by sc treatment.