Abstract
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 ord-lysine were included to vary net electric charge andd-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, lipophilicd-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.
Footnotes
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Send reprint requests to: J. R. Pappenheimer, Concord Field Station, Harvard University, Old Causeway Road, Bedford, MA 01730.
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↵1 This work was supported in part by a grant to J.R.P. from the American Heart Association. Labeling and HPLC of peptides were supported by National Institutes of Health Grant GM 15904 to J.E.M.
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↵2 Theoretically, the equilibrium partition coefficient (α), should be independent of relative volumes of the two phases. In practice we find that α increases almost in inverse proportion to the ratio of oil/aqueous volumes. We have no explanation for this phenomenon, which occurs in both vegetable and “mineral” hydrocarbon oils. For purposes of the present paper this unexpected property is inconsequential so long as the same volume ratio is used throughout.
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↵3 We use the term bile salts to denote bile components having steroid nuclei with free acidic groups, including taurocholic and glycocholic acids.
- Abbreviations:
- TFA
- trifluoroacetic acid
- CHO
- glucose or maltose
- GITC
- guanidylisothiocyanate
- HPLC
- high pressure liquid chromatography
- Received May 22, 1996.
- Accepted September 9, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
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