Oral absorption of peptides through the cobalamin (vitamin B12) pathway in the rat intestine

• Published in: Pharmaceutical research Vol. 17; no. 7; pp. 825 - 832
• Main Authors: ALSENZ, J, RUSSELL-JONES, G. J, WESTWOOD, S, LEVET-TRAFIT, B, DE SMIDT, P. C
• Format: Journal Article
• Language: English
• Published: New York, NY Springer 01.07.2000; Springer Nature B.V
• Subjects: Administration, Oral; Amino acids; Animals; Antibodies; Biological and medical sciences; Caco-2 Cells - metabolism; Cell culture; General pharmacology; Humans; Intestinal Absorption - physiology; Intestinal Mucosa - metabolism; Intrinsic Factor - metabolism; Ligands; Male; Medical sciences; Oral administration; Penicillin; Peptides - pharmacokinetics; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Physiology; Polypeptides; Rats; Rats, Wistar; Vitamin B 12 - pharmacokinetics; Australia; Intravenous administration; Peptides; Rat; Digestive system; Rodentia; Gut; Oral administration; In vitro; Cyanocobalamin; In vivo; Vertebrata; Mammalia; Absorption; Animal; Absorption enhancer; Conjugated compound; Pharmacokinetics
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1023/A:1007556108673

This study was aimed at examining the extent and mechanism of uptake of cobalamin (Cbl)-conjugated peptides in vitro and in vivo. To enable acquisition of quantitative absorption data of Cbl-peptides, metabolically stable octapeptides (DP3), with (Cbl-Hex-DP3) or without a hexyl spacer (Cbl-DP3), were coupled to Cbl and radiolabeled. For comparison, LHRH coupled to Cbl was used as metabolically susceptible peptide. Biological recognition of Cbl-peptides was studied in the physiological order: binding by Intrinsic Factor (IF), recognition and transport of the IF-complexes by IF-Cbl receptors (IFCR) on Caco-2 monolayers and oral absorption of the Cbl-conjugates in the rat. All Cbl-peptides bound to IF and the IF-complexes were recognized by IFCR receptors on Caco-2 monolayers. Binding was saturable and could be inhibited by a 20-fold excess of IF-Cbl, but not of Non-intrinsic Factor (NIF)-Cbl. Oral administration of these ligands to rats resulted in absorption of 53%, 45%, 42%, and 23% of the applied radioactivity for Cbl, Cbl-LHRH, Cbl-Hex-DP3, and Cbl-DP3, respectively. Simultaneous administration of a >10(5)-fold excess of unlabeled Cbl reduced uptake of all compounds to <4%. Tissue distribution and elimination of the metabolically stable Cbl-conjugates were comparable to Cbl. The endogenous Cbl uptake pathway can be exploited for oral peptide delivery as indicated by the specific and high (40-45%) uptake of metabolically stable Cbl-coupled octapeptides.