ABSORPTION AND EXCRETION OF UNDEGRADABLE PEPTIDES - ROLE OF LIPID SOLUBILITY AND NET CHARGE

Absorption and excretion of undegradable peptides were investigated wi th use of octapeptides synthesized from D-amino acids. D-Tyrosine was included in each peptide to permit labelling with I-125, D-glutamic ac id or D-lysine were included to vary net electric charge and D-serine or D-leucine were included to vary lipid solubility. Peptides were adm inistered parenterally or orally to normal rats drinking 5% glucose or maltose. Forty-five percent of a lipid-insoluble, negatively charged octapeptide added to the drinking fluid in milligram quantities was ab sorbed from the intestine and excreted intact in urine; 90% of this pe ptide was recovered in urine after parenteral injection, in contrast, lipophilic D-octapeptides were largely excreted in feces, even after s ubcutaneous injection; the amounts excreted in feces were correlated w ith oil/aqueous partition coefficients. Evidence is presented that lip ophilic peptides entering liver cells combine with bile salts to form hydrophilic complexes that are secreted rapidly at high concentration in bile. At physiological concentrations of bile salts (5-40 mM) and n anomolar concentrations of peptide the binding is so complete that the se undegradable peptides are rapidly cleared from liver to duodenal fl uid in association with the bile salts. After reaching the ileum the b ile salts are reabsorbed to blood, leaving the original lipophilic pep tides to be excreted in the feces from which they can be extracted, pu rified and identified by high-pressure liquid chromatography. These me chanisms are discussed in relation to a) the paracellular absorption o f peptides and other solutes by solvent drag and b) the delivery and f ate of biologically active peptides.