Intestinal absorption of peptides by coupling to bile acids.

Kramer, Werner; Wess, G.; Neckermann, Georg; Schubert, Gerrit Alexander; Fink, J; Girbig, Frank; Gutjahr, Ulrike; Kowalewski, Simone; Baringhaus, Karl‐Heinz; Böger, G

doi:10.1016/s0021-9258(17)34105-4

Cited by 77 publications

(16 citation statements)

References 39 publications

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“…Despite a large portion of their research focusing on the transporters in hepatocytes, they made great achievements in promoting drug absorption by ASBT as well. For example, they modified cholic acid at C 3 and C 24 to synthesize 3β-(ωaminoalkoxy)-7α, l2α-dihydroxy-5β-cholan-24-oic acid, conjugated it with peptides of different chain lengths, and tested their absorption after ileum perfusion in rats [112,113]. It was found that [ 3 H] taurocholate uptake was significantly reduced when incubated with hybrid peptides containing more than four amino acid residues.…”

Section: Bile Acid-conjugated Prodrug Strategymentioning

confidence: 99%

Bile acid transporter-mediated oral drug delivery

Deng

Bae

2020

Journal of Controlled Release

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Section: Bile Acid-conjugated Prodrug Strategymentioning

confidence: 99%

Bile acid transporter-mediated oral drug delivery

Deng

Bae

2020

Journal of Controlled Release

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“…The oligopeptides may be made enterally absorbable by coupling to modified bile acid molecules making use of the specific Na + /ileal acid cotransporter. This finding may be of importance for the design and development of orally active peptide drugs (Kramer et al, 1994).…”

Section: Bile Acid Transportermentioning

confidence: 75%

Drug Transport and Targeting

Oh¹,

Han²,

Amidon

2002

Pharmaceutical Biotechnology

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“…Inhibition of [ 14 C]TCA Transport by Bile Acid − Peptide Conjugates. The CaCo-2 cell system was chosen for this study because these cells functionally express the bile acid transporter ( , ). Since maximal expression of this carrier occurs after 21 days after seeding on transwell membranes, all experiments were carried with cells cultured for 21−28 days.…”

Section: Resultsmentioning

confidence: 99%

“…They showed that their conjugates were able to bind to the intestinal bile acid transporter but were not transported in vivo. More recently, Kramer and colleagues used modifications at the 3-position for liver specific targeting of chlorambucil (5), HMG-CoA reductase inhibitors (6), and small peptides up to 4 amino acids (7). The essential molecular requirement for active bile acid absorption is the retention of an acidic moiety around the 24-position on the sterol nucleus.…”

Section: Introductionmentioning

confidence: 99%

Enhanced Transepithelial Transport of Peptides by Conjugation to Cholic Acid

Swaan¹,

Hillgren²,

Szoka³

et al. 1997

Bioconjugate Chem.

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The potential of the intestinal bile acid transporter to serve as a shuttle for small peptide molecules was investigated. Eleven peptides with a 2-6 amino acid backbone were conjugated to the 24-position of 3 alpha, 7 alpha, 12 alpha-trihydroxy-5 beta-cholan-24-oic acid (cholic acid) via an amide bond using an automated peptide synthesizer. In a human intestinal cell line (CaCo-2), cholic acid-peptide conjugates were able to inhibit the transepithelial transport of [3H]taurocholic acid, a natural substrate for the bile acid carrier, at a 100:1 conjugate/substrate ratio. Affinity for the carrier decreased significantly when the conjugate in the 24-position increased from 1 to 2 amino acids. Further increase in the amino acid chain length caused only minor decrease in affinity. A tetrapeptide-bile acid conjugate, [3H]-ChEAAA (Ch = cholic acid), was transported by the bile acid transporter, showing markedly higher apical (AP)-to-basolateral (BL) compared to BL-to-AP transport and inhibition by a 100-fold excess taurocholic acid. Another conjugate with 6 amino acids (ChEASASA) was transported by a passive diffusion pathway but still showed higher transport rates than the passive permeability marker mannitol, suggesting the possibility that the cholic acid moiety aids the passive membrane transfer of peptide molecules by increasing its lipophilicity. Metabolism of bile acid-peptide conjugates in CaCo-2 cells was 3% over 3 h. In conclusion, these studies show that the coupling of peptides to the 24-position of the sterol nucleus in cholic acid results in a combination of decreased metabolism and increased intestinal absorption, either by a carrier-mediated pathway or by accelerated passive diffusion.

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Intestinal absorption of peptides by coupling to bile acids.

Cited by 77 publications

References 39 publications

Bile acid transporter-mediated oral drug delivery

Bile acid transporter-mediated oral drug delivery

Drug Transport and Targeting

Enhanced Transepithelial Transport of Peptides by Conjugation to Cholic Acid

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