ISSN:
1573-904X
Keywords:
cobalamin (vitamin B12)
;
in vitro-in vivo study
;
Cbl-peptide conjugate
;
oral absorption
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
Notes:
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.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1007556108673
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