The Catabolism of two Adrenocorticotrophin Analogues Following Intravenous Injection

Abstract

We have studied the catabolic fate, following intravenous injection in the rat, of two ACTH analogues, namely corticotrophin — (1–24)—tetracosapeptide (Synacthen ®, and [D-Ser1, Lys17,1] corticotrophin — (1–18)—Octadecapeptide amide (C-41795-Ba). Using the two analogues labelled with tritium in the tyrosine of position two it was established that C-41795-Ba has a much longer plasma and tissue half-life than Synacthen, as indicated by ion exchange chromatography of tissue extracts. This confirms results previously obtained with an isolated adrenal cell bioassay.1. There is a marked concentration of radioactivity in the kidneys with both peptides which consists in each case of intact peptide and several discrete fragments. However, the maximum concentration of Synacthen and its fragments occurs after 10 min and constitutes about 10% of the injected dose whilst C-41795-Ba and its fragments reach a maximum of about 30%, of the injected dose after 30 min which has declined by 60 min. The protection from exopeptidase attack, which the D-Seryl residue at the N-terminus and amidation at the C-terminus confer on C-41795-Ba, considerably enhances its half-life. The relative importance of the kidneys as organs of clearance and degradation is also quantitatively changed by these modifications.