title: Intestinal metabolism and absorption of cholecystokinin analogs in rats.
abstract: Intestinal metabolism and poor permeability were known to be major barriers for oral absorption of large peptide drugs. Dimensionless wall permeability values of C-terminal octa- and tetra-peptides cholecystokinin analogs (CCK8 and CCK4) were estimated and found out to be greater than 1, suggesting no permeability-limited absorption for CCK analogs. Thus, a strategy employing enzyme inhibitors and a specific delivery site to improve the absorption was developed and tested with CCK8, followed by identification of metabolites of the analogs and their participating enzymes in rabbit brush-border membrane vesicles. Thiorphan and amastatin, a specific enzyme inhibitor for enkephalinase and aminopeptidase, respectively, in pH 4 buffer solution were coadministered with CCK8 to the ileum in fistulated rats. The absolute bioavailability (F) of CCK8 was 5.4% and increased to 19% in the presence of the enzyme inhibitors, while the F values following oral administration were close to zero. These results indicate that peptide oral delivery is possible.
authors.affiliation: College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Sheng-Fang
authors.initials: SF
authors.lastname: Su
authors.forename: Gordon L
authors.initials: GL
authors.lastname: Amidon
authors.forename: Hye J
authors.initials: HJ
authors.lastname: Lee
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D005402:Fistula; D007082:Ileum / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D007408:Intestinal Absorption; D007583:Jejunum / Q000378:metabolism* / Q000601:surgery; D008871:Microvilli / Q000201:enzymology; D010455:Peptides / Q000008:administration & dosage; D010539:Permeability; D011480:Protease Inhibitors / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D012844:Sincalide / Q000008:administration & dosage* / Q000378:metabolism*; D013758:Tetragastrin / Q000008:administration & dosage* / Q000378:metabolism*; D015244:Thiorphan / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D010455:Peptides; D011480:Protease Inhibitors; D013758:Tetragastrin; C016977:amastatin; D015244:Thiorphan; D012844:Sincalide