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Intestinal absorption of peptides by coupling to bile acids
W Kramer1, G Wess, G Neckermann
1Hoechst Aktiengesellschaft, Frankfurt am Main, Germany.
The Journal of Biological Chemistry
|April 8, 1994
Summary
Attaching peptides to bile acids enables intestinal absorption via the bile acid transporter. This strategy enhances oral bioavailability for peptide drugs, overcoming poor absorption limitations.
Area of Science:
- Pharmacology
- Gastroenterology
- Drug Delivery
Background:
- Poor intestinal absorption of peptides limits their therapeutic use.
- Bile acids are efficiently absorbed via an active, Na(+)-dependent transport system in the ileum.
Purpose of the Study:
- To investigate if peptides can be made enterally absorbable by conjugating them to bile acids.
- To assess the mechanism of absorption for these peptide-bile acid conjugates.
Main Methods:
- Synthesized peptide-bile acid conjugates and tested their effect on Na(+)-dependent [3H]taurocholate uptake in rabbit ileal brush-border membrane vesicles.
- Utilized photoaffinity labeling to identify bile acid-binding proteins and assessed inhibition by conjugates.
- Performed in vivo ileum perfusion in rats to evaluate intestinal absorption and bile secretion of a fluorescent peptide-bile acid conjugate.
Main Results:
- Peptide-bile acid conjugates inhibited taurocholate uptake and photoaffinity labeling of ileal bile acid transporters.
- Absorption and inhibitory effects decreased with increasing peptide chain length.
- In vivo studies demonstrated intestinal absorption and bile secretion of a peptide-bile acid conjugate, unlike the parent peptide.
Conclusions:
- Oligopeptides can be rendered enterally absorbable by conjugation to modified bile acids.
- This approach leverages the ileal bile acid transporter for peptide drug delivery.
- This strategy holds significant potential for developing orally active peptide therapeutics.