Strategies for Increasing Drug Absorption Targeting Transporters

Strategies for Increasing Drug Absorption Targeting Transporters 

Different strategies for targeting intestinal transporters to increase intestinal permeability have been described  

Various strategies for exploitation or limitation of the impact of transporters are available for the discovery and development of drug candidates. Most often, the impact of transporters has been realized retrospectively. However, as knowledge increases on transporter expression and function, genomics of transporter, SAR, and protein structure, the basis for a rational design of substrates or inhibitors of transporter activity is enhanced. 

The transporter does also accept some dipeptides with a N-methylated peptide bond exemplified by Gly-Sar and some tripeptides with N-methylated amide bond however, N-methylation does not seem to be a general stabilization approach, since the affinity for PEPT1 is not retained for all the investigated compounds [113, 114], 

Absolute affinities (X -values) for natural di- and tripeptides are normally in the range ofO.1-3 mM. To evaluate relevant affinity values, Brandsch and coworkers have proposed the following classification X 0.5mM is high affinity, 0.5 X 5 is medium affinity, and X 5 is low affinity, and values above 15 mm seem to be irrelevant [5]. The latter is probably based on the observation made with 3-lactam antibiotics where the oral bioavailability seems to be at least partly mediated via PEPT1-mediated transport, and a threshold of 15 mm was proposed [8]. 

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