Absorption and excretion of undegradable peptides: role of lipid solubility and net charge.

Absorption and excretion of undegradable peptides were investigated with use of octapeptides synthesized from D-amino acids. D-Tyrosine was included in each peptide to permit labeling with 125I, D-glutamic acid or D-lysine were included to vary net electric charge and D-serine or D-leucine were included to vary lipid solubility. Peptides were administered 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 absorbed from the intestine and excreted intact in urine; 90% of this peptide was recovered in urine after parenteral injection. In contrast, lipophilic D-octapeptides were largely excreted in feces, even after subcutaneous injection; the amounts excreted in feces were correlated with oil/aqueous partition coefficients. Evidence is presented that lipophilic 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 nanomolar concentrations of peptide the binding is so complete that these undegradable peptides are rapidly cleared from liver to duodenal fluid in association with the bile salts. After reaching the ileum the bile salts are reabsorbed to blood, leaving the original lipophilic peptides to be excreted in the feces from which they can be extracted, purified and identified by high-pressure liquid chromatography. These mechanisms are discussed in relation to a) the paracellular absorption of peptides and other solutes by solvent drag and b) the delivery and fate of biologically active peptides.