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Thiodipeptides targeting the intestinal oligopeptide transporter as a general approach to improving oral drug delivery

Foley, David W.; Pathak, Ravindra B.; Phillips, Theresa R.; Wilson, Gayle L.; Bailey, Patrick D.; Pieri, Myrtani; Senan, Anish; Meredith, David

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Authors

David W. Foley

Ravindra B. Pathak

Gayle L. Wilson

Patrick D. Bailey

Myrtani Pieri

Anish Senan

David Meredith



Abstract

The broad substrate capacity of the intestinal oligopeptide transporter, PepT1, has made it a key target of research into drug delivery. Whilst the substrate capacity of this transporter is broad, studies have largely been limited to small peptides and peptide-like drugs. Here, we demonstrate for the first time that a diverse range of drugs can be targeted towards transport by PepT1 using a hydrolysis resistant carrier. Eleven prodrugs were synthesized by conjugating modified dipeptides containing a thioamide bond to the approved drugs ibuprofen, gabapentin, propofol, aspirin, acyclovir, nabumetone, atenolol, zanamivir, baclofen and mycophenolate. Except for the aspirin and acyclovir prodrugs, which were unstable in the assay conditions and were not further studied, the prodrugs were tested for affinity and transport by PepT1 expressed in Xenopus laevis oocytes: binding affinities ranged from approximately 0.1 to 2?mM. Compounds which showing robust transport in an oocyte trans stimulation assay were then tested for transcellular transport in Caco-2?cell monolayers: all five tested prodrugs showed significant PepT1-mediated transcellular uptake. Finally, the ibuprofen and propofol prodrugs were tested for absorption in rats: following oral dosing the intact prodrugs and free ibuprofen were measured in the plasma. This provides proof-of-concept for the idea of targeting poorly bioavailable drugs towards PepT1 transport as a general means of improving oral permeability.

Journal Article Type Article
Acceptance Date Jun 28, 2018
Online Publication Date Jun 30, 2018
Publication Date Aug 5, 2018
Publicly Available Date May 26, 2023
Journal European Journal of Medicinal Chemistry
Print ISSN 0223-5234
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 156
Pages 180-189
DOI https://doi.org/10.1016/j.ejmech.2018.06.064
Keywords Prodrug, Membrane transporter, Intestine, PepT1, Drug delivery
Publisher URL http://dx.doi.org/10.1016/j.ejmech.2018.06.064

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