Metabolism of vasopressin, oxytocin, and their analogues in the human gastrointestinal tract.

The bioavailability from the gastrointestinal tract of peptides as large as nonapeptides is very low, which may be attributed to extensive lumenal and mucosal degradation. The aim of the present study was to investigate the stability of the neurohypophyseal hormones arginine-vasopressin (AVP), oxytocin (OT), and their synthetic analogues in human intestinal contents, small intestinal brush-border membranes, and gastric, rectal, and colonic plasma membranes. Peptides were incubated in gastrointestinal contents from healthy volunteers and in human intestinal mucosa homogenates. The extent of degradation was determined by reversed-phase high performance liquid chromatography (HPLC). AVP was rapidly degraded in the ileum fractions of the intestinal contents whereas 50% of the analogue 1-deamino-8-D-arginine vasopressin (dDAVP) remained intact after 35 min. The degradation was pH dependent, and a concentration-dependent inhibition was observed when aprotinin, a proteinase inhibitor, was preincubated with contents from the ileum. No degradation of AVP, dDAVP, or oxytocin analogues was observed in the mucosa homogenate from the stomach. The peptides were found to be rather slowly degraded by intestinal microvilli membranes and colonic and rectal plasma membranes. This degradation occurred essentially when reduced glutathione 10(-4) M was added to the incubations. In conclusion, the major enzymatic barrier to intestinal absorption of OT, VP, and their analogues is present in the intestinal juice and not in the mucosa, which, however, constitutes a major physical barrier to peptide transport.