RADIOIMMUNOASSAY OF METERELIN AND PHARMACOKINETICS AFTER SINGLE INJECTION AND IMPLANT ADMINISTRATION IN DOGS

A sensitive and specific radioimmunoassay for a novel luteinizing-horm one-releasing-hormone (LHRH) agonist, [2-Me-D-Trp(6), DesGly(10)]LHRH ethylamide (meterelin), was developed for documenting the pharmacokine tic parameters of this peptide following its intravenous (iv) and subc utaneous (sc) administration in dogs. The assay was also used for moni toring meterelin in plasma following its release from d,l-lactide-glyc olide implants in the same species. Rabbit antisera generated against [DespyroGlu(1)] meterelin and conjugated to bovine serum albumin with glutaraldehyde showed high specificity, whereas crossreactivity to LHR H and its fragments and to analogs with substitutions at residues 6 an d 10 was found insignificant. The assay was validated in terms of accu racy (recovery range, 94.0-105.4%), in terms of precision (intra- and interassay variations of 10.0-12.4% and 8.6-11.3%, respectively), and in terms of sensitivity (minimum detectable dose of 2.7 pg/assay). Fol lowing iv acute administration, a biexponential decline of plasma mete relin levels was observed, with distribution and elimination half-live s of 5.9 +/- 2.5 and 106 +/- 22 min, respectively. After sc acute admi nistration, the elimination half-life was in the range of 103 to 173 m in. The systemic clearance (CL(T)) ranged from 1.6 to 2.6 mL/min/kg, a nd the volume of distribution at steady state (Vd(ss)) varied from 285 to 438 mL/kg. The elimination half-life (T-1/2 beta), Vd(s)s, and Cl- T were not significantly different after both routes of administration over the 1-100-mu g/kg dose range of peptide studied. Castrate levels of testosterone were attained 10 days after sc administration of the implant, lasted for up to 247 days, and were well correlated with plas ma levels of meterelin.