COMPARISON OF THE PHARMACOKINETICS IN MAN OF TWO SYNTHETIC ACTH ANALOGES: a1–24 AND SUBSTITUTED β1–18 ACTH.

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Abstract
SUMMARY: The synthetic substituted corticotrophin analogue, a1–18 ACTH, was given intravenously or subcutaneously to thirteen human volunteers in whom endogenous secretion of ACTH had been suppressed with dexamethasone. Plasma levels of a1–18 ACTH over the succeeding 12–24 h were determined by radioimmunoassay and bioassy, together with the fluorometric corticosteroid responses. The plasma disappearance rate of a1–18 ACTH was compared with that of the corticotrophin fragment, a1–24 ACTH (tetracosactrin, Synacthen), in both unmodified and depot forms.Plasma levels of a1–18 ACTH were higher and were detectable for longer after intravenous rather than subcutaneous administration. The higher levels were associated with greater and more prologed corticosteroid responses. In addition, the corticosteroid response to the intravenous injection of 1 mg of a1–18 was greater and more prolonged than the response to the intravenous injection of the same dose of a1–24 ACTH. The plasma levels of immunoreactive a1–24 ACTH were not detectable for more than 4 h after this dose. After the intramuscular administration of 1 mg of the depot preparation, however, detectable plasma levels persisted for 12 h. It is concluded that the brief corticotrophic activity of unmodified a1–24 ACTH is due mainly to its rapid clearance from the circulation.There was no significant dissociation between the disappearance rates of immuno‐ and bio‐active a1–18 ACTH. This contrasted with a1–24 ACTH whose bioactivity disappeared from plasma significantly faster than immunoreactivity. This difference probably reflects the greater stability of a1‐18 ACTH In the circulation and this in turn accounts, in part at least, for its prolonged corticotrophic activity.In a separate study the peptides were given intranasally through special applicators to eleven dexamethasone suppressed volunteers. The plasma levels of a1–18 ACTH after a 1 mg dose were lower than when given by other routes but the corteroid response was unaltered. The corticosteroid response to a 1 mg dose of intranasal a1–24 ACTH was brief and similar to that which followed an intavenous or subcutaneous injection; it was not significantly prolonged if 5 mg was given. It is concluded that intranasal a1–24 ACTH is unlikely to be of value but itranasal a1–18ACTH may be therapeutically useful.