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

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 showed 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.

Pharmacokinetics of Baclofen in a Full-Term Newborn after Intrauterine Exposure: A Case Report

“…At birth, the fetal-to-maternal plasma exposure ratio based on the area under the curve was 0.85, suggesting a good placental transfer of baclofen at this stage of pregnancy as expected with the low plasma protein binding of baclofen at 30%. Moreover, monocarboxylate and peptide-1 transporters expressed in the placenta [7,8] might increase baclofen transfer through the placenta [9]. After birth, baclofen plasma concentrations in the neonate decreased in a mono-exponential manner, as reported in adults [10].…”

Transporter-Mediated Drug Delivery

“…An interesting strategy was the development of a dipeptide-like thiopeptide “carrier”, which is a small molecule binder of PEPT1 that was intended to be used as a general drug carrier [ 321 ]. This carrier was chemically conjugated to several different drugs, and many of the conjugates showed high-affinity binding to PEPT1 and the ability to permeate into cells and through a Caco-2 cellular monolayer [ 322 , 335 ].…”

Transporter-Mediated Drug Delivery

“…An interesting strategy was the development of a dipeptide-like thiopeptide "carrier", which is a small molecule binder of PEPT1 that was intended to be used as a general drug carrier [317]. This carrier was chemically conjugated to several different drugs and many of the conjugates showed high-affinity binding to PEPT1 and the ability to permeate into cells and through a Caco-2 cellular monolayer [318,331].…”