COMPARISON OF PHARMACOKINETICS IN MAN OF 2 SYNTHETIC ACTH ANALOGS - ALPHA-1-24 AND SUBSTITUTED ALPHA1-18 ACTH

The synthetic substituted corticotrophin analogue .alpha.1-18 ACTH was given i.v. or s.c. to 13 human volunteers in whom endogenous secretion of ACTH had been suppressed with dexamethasone. Plasma levels of .alpha.1-18 ACTH over the succeeding 12-24 h were determined by radioimmunoassay and bioassay, together with the fluorometric corticosteroid responses. The plasma disappearance rate of .alpha.1-18 ACTH was compared with that of the corticotrophin fragment .alpha.1-24 ACTH (tetracosactrin, Synacthen) in both unmodified and depot forms. Plasma levels of .alpha.1-18 ACTH were higher and detectable for longer after i.v. rather than s.c. administration. The higher levels were associated with greater and more prolonged corticosteroid responses. In addition the corticosteroid response to the i.v. injection of 1 mg of .alpha.1-18 was greater and more prolonged than the response to the i.v. injection of the same dose of .alpha.1-24 ACTH. The plasma levels of immunoreactive .alpha.1-24 ACTH were not detectable for more than 4 h after this dose. After the i.m. administration of 1 mg of the depot preparation detectable plasma levels persisted for 12 h. The brief corticotrophic activity of unmodified .alpha.1-24 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 .alpha.1-18 ACTH. this contrasted with .alpha.1-24 ACTH whose bioactivity disappeared from plasma significantly faster than immunoreactivity. This difference probably reflects the greater stability of .alpha.1-18 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 11 dexamethasone suppressed volunteers. The plasma levels of .alpha.1-18 ACTH after a 1 mg dose were lower than when given by other routes but the corticosteroid response was unaltered. The corticosteroid response to a 1 mg dose of intranasal .alpha.1-24 ACTH was brief and similar to that which followed an i.v. or s.c. injection; it was not significantly prolonged if 5 mg was given. Intranasal .alpha.1-24 ACTH is unlikely to be of value but intranasal .alpha.1-18 ACTH may be therapeutically useful.