Abstract
Purpose. This study was aimed at examining the extent and mechanismof uptake of cobalamin (Cbl)-conjugated peptides in vitro and in vivo.
Methods. To enable acquisition of quantitative absorption data ofCbl-peptides, metabolically stable octapeptides (DP3), with (Cbl-Hex-DP3)or without a hexyl spacer (Cbl-DP3), were coupled to Cbl andradiolabeled. For comparison, LHRH coupled to Cbl was used as metabolicallysusceptible peptide. Biological recognition of Cbl-peptides was studiedin the physiological order: binding by Intrinsic Factor (IF), recognitionand transport of the IF-complexes by IF-Cbl receptors (IFCR) onCaco-2 monolayers and oral absorption of the Cbl-conjugates in the rat.
Results. All Cbl-peptides bound to IF and the IF-complexes wererecognized by IFCR receptors on Caco-2 monolayers. Binding wassaturable and could be inhibited by a 20-fold excess of IF-Cbl, but notof Non-intrinsic Factor (NIF)-Cbl. Oral administration of these ligandsto rats resulted in absorption of 53%, 45%, 42%, and 23% of theapplied radioactivity for Cbl, Cbl-LHRH, Cbl-Hex-DP3, and Cbl-DP3,respectively. Simultaneous administration of a >105-fold excess ofunlabeled Cbl reduced uptake of all compounds to <4%. Tissuedistribution and elimination of the metabolically stable Cbl-conjugates werecomparable to Cbl.
Conclusions. The endogenous Cbl uptake pathway can be exploitedfor oral peptide delivery as indicated by the specific and high (40–45%)uptake of metabolically stable Cbl-coupled octapeptides.
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Alsenz, J., Russell-Jones, G.J., Westwood, S. et al. Oral Absorption of Peptides Through the Cobalamin (Vitamin B12) Pathway in the Rat Intestine. Pharm Res 17, 825–832 (2000). https://doi.org/10.1023/A:1007556108673
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DOI: https://doi.org/10.1023/A:1007556108673