title: Intestinal absorption of the octapeptide SMS 201-995 visualized by fluorescence derivatization.
abstract: The absorption of an intact oligopeptide was investigated in rat and dog small intestine using the metabolically stable somatostatin analogue SMS 201-995. The synthetic octapeptide was coupled to 4-nitrobenzo-2-oxa-1,3-diazol to have a fluorescent label for the direct visualization. The 4-nitrobenzo-2-oxa-1,3-diazol-labeled peptide was active in displacing the corresponding hormone 125I-Tyr3-SMS 201-995 (Sandostatin; Sandoz Pharmaceuticals, Basel, Switzerland) from its high-affinity binding site in rat cortex membranes with an IC50 = 4.6 x 10(-10) mol/L. The release of growth hormone from cultured anterior pituitary cells was inhibited by the fluorescent somatostatin analogue with the same potency as by somatostatin 14 (IC50 = 6 x 10(-10) mol/L). Incubation with mucosal scrapings followed by high-performance thin-layer chromatography analysis showed that the peptide was stable against proteolysis. 4-Nitrobenzo-2-oxa-1,3-diazol SMS 201-995 was well absorbed from enterocytes of rat small intestine. The absorption was highest into jejunal cells and it could be inhibited by an excess of unlabeled peptide. A significantly lower absorption was detected in crypts compared with villus tips. No fluorescence could be seen in intestinal mucin and goblet cells. After oral administration, the 4-nitrobenzo-2-oxa-1,3-diazol-labeled peptide rapidly appeared in the blood of rats and dogs, reaching a bioavailability of 4.3% and maintaining pharmacological activity. This suggests that enterocytes are able to absorb intact oligopeptides being stabilized against proteolytic degradation through a transcellular mechanism.
authors.affiliation: Drug Delivery Systems and Preclinical Research, Sandoz Pharma Ltd., Basel, Switzerland.
authors.forename: G
authors.initials: G
authors.lastname: Fricker
authors.forename: C
authors.initials: C
authors.lastname: Bruns
authors.forename: J
authors.initials: J
authors.lastname: Munzer
authors.forename: U
authors.initials: U
authors.lastname: Briner
authors.forename: R
authors.initials: R
authors.lastname: Albert
authors.forename: T
authors.initials: T
authors.lastname: Kissel
authors.forename: J
authors.initials: J
authors.lastname: Vonderscher
mesh_terms: D000818:Animals; D001682:Biological Availability; D001692:Biological Transport / Q000502:physiology; D004285:Dogs; D005456:Fluorescent Dyes; D007082:Ileum / Q000378:metabolism; D007408:Intestinal Absorption / Q000502:physiology*; D007583:Jejunum / Q000378:metabolism*; D008297:Male; D008856:Microscopy, Fluorescence; D015282:Octreotide / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D011863:Radioimmunoassay; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D005456:Fluorescent Dyes; D015282:Octreotide