DISPOSITION OF H-3 LABELED BUSERELIN CONTINUOUSLY INFUSED INTO RATS

The disposition of the gonadotropin-releasing hormone (GnRH) agonist b userelin was studied in male rats under conditions of longterm adminis tration. Rats were continuously infused with about 30 pmole [H-3]-buse relin/24 h subcutaneously by osmotic minipumps for 4-7 days. After kil ling the rats, the H-3-activity of the tissues was measured and was fo und to be highly concentrated (about 10-fold to plasma) only in the pi tuitary. The daily amounts of H-3-activity excreted in urine and faece s were constant over the whole infusion period, suggesting steady stat e conditions. On a molar basis, of the infused dose of buserelin, 14.8 % was found to be excreted into urine as intact peptide, and 16.5, 10. 8 and 20.6% as the partial buserelin sequences 1-2, 1-3 and 5-9. It is concluded that the major elimination route of buserelin, constant wit h time, is glomerular filtration, followed by enzymatic degradation of part of the filtered peptide by kidney tubuli enzymes to the partial sequences 1-2, 1-3 and 5-9, which reflects the proteolytic breakdown o f buserelin by kidney membrane peptidases in vitro. Based on the simil arities in the pharmacokinetics, in vivo metabolites, and in vitro enz ymatic degradabilities among the GnRH agonists that have the native Gn RH sequence modified at position 6 with or without additional modifica tion at the C-terminal, the elimination process as shown here for buse relin should also be valid for other GnRH agonists.