Improvement of intestinal peptide absorption by a synthetic bile acid derivative, cholylsarcosine

The potential of the nontoxic bile salt derivative, cholylsarcosine, to enh ance the intestinal absorption of peptides was investigated in vitro and in situ. The permeation of the two model peptides octreotide and vasopressin- [arg(8)] (desmopressin) and the paracellular marker FITC-Dextran 4000 acros s Caco-2 cell (originally derived from a human colorectal carcinoma) monola yers was studied in the absence and in the presence of bile acids, includin g cholylsarcosine (CS). The absorption of the peptides was also determined in situ in rats. The absolute absorption efficiency was calculated by deter mination of plasma levels after intravenous administration of the peptides. Cytotoxic properties of the bile acids were studied using the following as says: WST-1-transformation measuring mitochondrial dehydrogenase activity a s an indicator of cell proliferation and cell viability, lactate dehydrogen ase (LDH) release by the Caco-2 cells and assessment of the transepithelial electrical resistance. CS, cholyltaurine (CT) and chenodeoxycholic acid (C DCA) showed an enhancing effect on peptide permeation across Caco-2 cell mo nolayers with the rank order CDCA>CT greater than or equal to CS, whereas u rsodeoxycholic acid exhibited no absorption enhancement. Determination of t he cytotoxic potential of the bile salts revealed the same rank order. In r ats, octreotide and desmopressin were absorbed from the gastrointestinal-tr act with moderate absorption efficiency. Coadministration of bile salts res ulted in an increased absorption efficiency. The effect of CS was similar t o that of CT. In conclusion, CS shows absorption enhancement properties and a relatively low cytotoxicity. It offers an alternative as absorption enha ncer as compared to conventional bile acids which may have a potential coca rcinogenic risk. (C) 2000 Elsevier Science B.V. All rights reserved.