Enantiomeric cyclic peptides with different Caco-2 permeability suggest carrier-mediated transport.
Recently, oral absorption of cyclic hexapeptides was improved by N-methylation of their backbone amides. However, the number and position of N-methylations or of solvent exposed NHs did not correlate to intestinal permeability, measured in a Caco-2 model. In this study, we investigate enantiomeric pairs of three polar and two lipophilic peptides to demonstrate the participation of carrier-mediated transporters. As expected, all the enantiomeric peptides exhibited identical lipophilicity (logD7.4) and passive transcellular permeability determined by the parallel artificial membrane permeability assay (PAMPA). However, the enantiomeric polar peptides exhibited different Caco-2 permeability (Papp) in both directions a-b and b-a. The same trend was observed for one of the lipophilic peptide, whereas the second lipophilic enantiomer pair showed identical Caco-2 permeability (within the errors). These findings provide the first evidence for the involvement of carrier-mediated transport for peptides, especially for those of polar nature.
Institute for Advanced Study and Center for Integrated Protein Science at the Technische Universität München, Department Chemie, Lichtenbergstrasse 4, 85747 Garching (Germany).
Udaya Kiran
UK
Marelli
Institute of Molecular Pharmacy, University of Basel, Klingelbergstrasse 50, 4056 Basel (Switzerland).
Jacqueline
J
Bezençon
Institute for Advanced Study and Center for Integrated Protein Science at the Technische Universität München, Department Chemie, Lichtenbergstrasse 4, 85747 Garching (Germany).
Eduard
E
Puig
Institute of Molecular Pharmacy, University of Basel, Klingelbergstrasse 50, 4056 Basel (Switzerland). beat.ernst@unibas.ch.
Beat
B
Ernst
Institute for Advanced Study and Center for Integrated Protein Science at the Technische Universität München, Department Chemie, Lichtenbergstrasse 4, 85747 Garching (Germany). kessler@tum.de.
Horst
H
Kessler
D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D015195:Drug Design; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D008567:Membranes, Artificial; D008745:Methylation; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000493:pharmacokinetics*; D010539:Permeability; D013237:Stereoisomerism
D008567:Membranes, Artificial; D010456:Peptides, Cyclic
conformation; cyclic peptides; enantioselecitivity; intestinal permeability; oral availability