Summary
The disposition of the gonadotropin-releasing hormone (GnRH) agonist buserelin was studied in male rats under conditions of long-term administration. Rats were continuously infused with about 30 pmole [3H]-buserelin/24 h subcutaneously by osmotic minipumps for 4–7 days. After killing the rats, the3H-activity of the tissues was measured and was found to be highly concentrated (about 10-fold to plasma) only in the pituitary. The daily amounts of3H-activity excreted in urine and faeces were constant over the whole infusion period, suggesting steady state 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 with 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 of buserelin by kidney membrane peptidases in vitro. Based on the similarities in the pharmacokinetics, in vivo metabolites, and in vitro enzymatic degradabilities among the GnRH agonists that have the native GnRH sequence modified at position 6 with or without additional modification at the C-terminal, the elimination process as shown here for buserelin should also be valid for other GnRH agonists.
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Heinrich, N., Albrecht, E., Sandow, J. et al. Disposition of3H-labelled buserelin continuously infused into rats. European Journal of Drug Metabolism and Pharmacokinetics 21, 345–350 (1996). https://doi.org/10.1007/BF03189737
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DOI: https://doi.org/10.1007/BF03189737