Intestinal absorption of peptides by coupling to bile acids

• Published in: The Journal of biological chemistry Vol. 269; no. 14; pp. 10621 - 10627
• Main Authors: KRAMER, W, WESS, G, ENHSEN, A, FALK, E, FRIEDRICH, M, GLOMBIK, H, HOFFMANN, A, PITTIUS, C, URMANN, M, NECKERMANN, G, SCHUBERT, G, FINK, J, GIRBIG, F, GUTJAHR, U, KOWALEWSKI, S, BARINGHAUS, K.-H, BÖGER, G
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Biochemistry and Molecular Biology 08-04-1994
• Subjects: Amino Acid Sequence; Animals; Bile Acids and Salts - metabolism; Biological and medical sciences; Biological Transport; Cell physiology; Fundamental and applied biological sciences. Psychology; Ileum - metabolism; In Vitro Techniques; Intestinal Absorption; Male; Membrane and intracellular transports; Molecular and cellular biology; Molecular Sequence Data; Peptides - metabolism; Rabbits; Rats; Rats, Wistar; Delivery system; Vertebrata; Absorption; Mammalia; Peptides; Bile acid; Substrate specificity; Gut; Coupling; Carrier protein
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/S0021-9258(17)34105-4

Poor intestinal absorption of peptides greatly limits their use as drugs for the treatment of chronic diseases. Since bile
acids are efficiently absorbed by an active, Na(+)-dependent transport system in the ileum of mammals, model peptides of different
chain length were attached to the 3-position of modified 3 beta-(omega-amino-alkoxy)-7 alpha, 12 alpha-dihydroxy-5 beta-cholan-24-oic
acid. These peptide-bile acid conjugates inhibited Na(+)-dependent [3H]taurocholate uptake into brush-border membrane vesicles
isolated from rabbit ileum in a concentration-dependent manner. Furthermore, photoaffinity labeling of the bile acid-binding
proteins of M(r) 93,000 and 14,000, identified as the protein components of the ileal Na(+)-dependent bile acid transport
system in rabbit ileum (Kramer, W., Girbig, F., Gutjahr, U., Kowalewski, S., Jouvenal, K., Müller, G., Tripier, D., and Wess,
G. (1993) J. Biol. Chem. 268, 18035-18046) by the photoreactive taurocholate analogue, (3,3-azo-7 alpha, 12 alpha-dihydroxy-5
beta [7 beta, -12 beta-3H]cholan-24-oyl)-2-aminoethanesulfonic acid, was inhibited by the peptide-bile acid conjugates. In
contrast, the parent peptides and amino acids neither had a significant effect on [3H]taurocholate uptake by ileal brush-border
membrane vesicles nor on photoaffinity labeling of the ileal bile acid-binding membrane proteins. The inhibitory effect of
peptide-bile acid conjugates on [3H]taurocholate transport and photoaffinity labeling of the bile acid-binding proteins in
rabbit ileal vesicles decreased with increasing chain length of the attached peptide radical. By in vivo ileum perfusion in
anesthetized rats an intestinal absorption of the bile acid conjugate S3744 of the fluorescent oxaprolylpeptide 4-nitrobenzo-2-oxa-1,3-diazol-beta-Ala-Phe-5-Opr-Gly
(S1037) and secretion of the intact compound into bile could be demonstrated, whereas the parent peptide S1037 or its t-butylester
S4404 were not absorbed. The intestinal absorption of S3744 showed a similar temperature dependence as [3H]taurocholate absorption
and was inhibited by the presence of taurocholate indicating a carrier-mediated uptake of S3744 via the ileal bile acid transporter.
In conclusion, these results indicate that oligopeptides can be made enterally absorable by coupling to modified bile acid
molecules making use of the specific intestinal absorption pathway for bile acids. This finding may be of great importance
for the design and development of orally active peptide drugs.