On the metabolism of two adrenocorticotrophin analogues.

The metabolism of Synacthen (corticotrophin-(1--24)-tetracosapeptide) and C-41795-Ba ([D-Ser1,Lys17,Lys18]-corticotrophin-(1--18)-octadecapeptide amide) have been compared in the rat following intravenous injection. Using Synacthen and C-41795-Ba labelled with tritium it was possible to follow the tissue distribution of the two peptides. The kidney was shown to concentrate intact peptide and fragments of both peptides. Autoradiography of perfused kidney sections demonstrated the uptake of radioactivity into the lysosomes of the kidney proximal tubule cells. Comparison of the distribution of radioactive products formed from the tetracosapeptide labelled in different positions indicates that, prior to renal uptake, metabolism is taking place at other sites in the body. It is suggested that rapid cleavage occurs extracellularly at or near the N- and C-termini. Then large fragments remaining in the circulation, together with any intact material, are filtered through the glomerulus and are taken up by endocytosis into the proximal tubule cells of the kidney. The synthetic N- and C-terminal protection of the octadecapeptide appears to inhibit the extracellular attack and so the concentration of intact peptide in the kidneys is initially higher than the tetracosapeptide. Although concentrations of radioactivity in other tissues are low in comparison with the kidneys, the quantities are quite high when the weight of the tissues are considered. Chromatographic analysis of this radioactivity reveals that the octadecapeptide gives rise to much higher tissue levels of intact peptide and we believe that this acts as a depot and gives rise to the sustained blood concentrations and prolonged biological effects observed with this peptide.