Tight junctions and drug absorption
up in the gastrointestinal tract. All attempts to solve this
problem have thus far resulted in unacceptable risks of side
effects, mainly because the intestinal wall is so severely impacted
that not only the drug but other substances, including toxins, can
be absorbed. Now a team of scientists from Uppsala University in
Sweden have made a discovery that may solve the problem.
The intestinal wall functions as an effective obstacle to keep various substances from passing from the intestine out into the body. Some drugs, like antibiotics, can pass through structures called tight junctions between the epithelial cells lining the GI tract and be absorbed, but many other important medicines cannot.
Tight junctions consist mainly of two types of proteins: claudins and occludins. Each of these protein molecules interacts with a corresponding molecule in the adjacent cell by a loop-shaped bond consisting of peptides. To let more substances pass through, researchers have tried to interfere with the bonds between these proteins and increase the 'porosity' of the intestinal wall.
Thus far research has been directed toward changing the porosity via the claudins, which are easier to manipulate, but so far this has led to undesirable and irreversible effects that increase the risk of cell damage.
Instead, the Uppsala scientists, led by Prof Per Artursson, have focused on the other protein: the occludins, which are more static proteins. They describe in the journal Molecular Pharmacology how they synthesised peptides that bind to different sequences in the loop that joins the canal between two cells.
In vitro experiments have shown that one of the peptides was able to increase the porosity of the intestinal wall when it was coupled with occludin molecules, but only from the side furthest from the intestinal tract. From the other side, i.e. in the lumen of the intestine, the molecules lumped together or were destroyed by enzymes before they had time to affect the filter.
However, the research team went one step further. By adding a fatty acid as a shield for the peptide part, they managed to increase the porosity from the lumenal side, suggesting that it may be possible to dose the peptides alongside other drugs to improve their oral absorption.
The scientists also succeeded in modifying the impact on the intestinal wall, from rapid and short loosening of the tight junctions to a longer-lasting effect.
In an editorial accompanying the study, Kim Barett of the University of California in the US comments that the discovery "seems likely to allow for the oral delivery of a wide variety of agents for which this previously was not possible, and thus the development of new and more effective therapeutic options for a wide range of human diseases."
Source: Molecular Pathology December issue
