N-acetyl oxyntomodulin30-37: pharmacokinetics and activity on gastric acid secretion.
Oxyntomodulin, an intestinal hormone which inhibits gastric acid secretion, is composed of glucagon and a C-terminal octapeptide. This octapeptide mimics the biological activity of the hormone. We have studied the activity of the N-acetyl octapeptide, partially protected against enzymatic degradation, on pentagastrin-, histamine- and milk meal-stimulated secretion in conscious rats and compared it to that of oxyntomodulin and its derivatives. The N-acetylated octapeptide had a 3-fold higher potency than the octapeptide on pentagastrin-stimulated secretion. On histamine-stimulated secretion, the differences between the acetylated and the free octapeptides were that the former displayed a dose-response curve parallel to that of oxyntomodulin and a 4-fold higher potency. The increase in potency appears to be related in part to a decrease in the metabolic clearance rate in vivo (6-fold) and, in vitro, to an increase in half-life (3-fold) when incubated with rat liver plasma membranes. Similarly to the free octapeptide, the acetylated form decreased acid secretion stimulated by a milk meal, when infused before the meal. Acetylation of the Lysine side chains resulted in a totally inactive molecule. The results indicate that acetylating the N-terminus of the octapeptide of oxyntomodulin increases the similarities with the natural hormone.(ABSTRACT TRUNCATED AT 250 WORDS)
Carles-Bonnet
C
C
Centre CNRS-INSERM de Pharmacologie Endocrinologie, Montpellier, France.
Jarrousse
C
C
Niel
H
H
Martinez
J
J
Rolland
M
M
Bataille
D
D
D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D005744:Gastric Acid / Q000378:metabolism*; D004763:Glucagon-Like Peptides / Q000493:pharmacokinetics* / Q000494:pharmacology; D006632:Histamine / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D053772:Oxyntomodulin; D010418:Pentagastrin / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D053772:Oxyntomodulin; D004763:Glucagon-Like Peptides; D006632:Histamine; D010418:Pentagastrin