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Discovery can make it possible to take more drugs orally
December 01, 2003Many drugs cannot be administered orally since they cannot be taken up by the intestines. 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 major 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 use the transport canals that exist, while other important medicines cannot. The porosity of the intestinal wall is determined by a sort of "filter," so-called "tight junctions," consisting mainly of two types of proteins: claudins and occludins. Each such protein molecule interacts with a corresponding molecule in the adjacent cell by a loop-shaped bond consisting of peptides. To let more substances pass through, it's necessary to temporarily increase the porosity of the filter--without damaging the cell. Thus far research has been directed toward changing the porosity via the claudins, which are more dynamic and changeable, but this has always brought with it undesired and irreversible effects that increase the risk of cell damage.
Instead, the Uppsala scientists, led by Professor Per Artursson, have focused on the other protein: the occludins, which are more static proteins. Experiments have been carried out on cells and have yet to be applied to living organisms. They synthesized peptides that correspond to different sequences in the loop that joins the canal between two cells. One of these peptides proved to increase the porosity of the intestinal wall when it was coupled with occludin molecules, but only from one side of the wall. From the other side, corresponding to the one from the intestine out into the body, the molecules proved to lump together or to be destroyed by enzymes before they had time to affect the filter. But 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 other side as well. What's more, the scientists succeeded in guiding the effect on the intestinal wall, from rapid and short to a longer lasting impact.
The editorial in the December issue of the prestigious journal Molecular Pharmacology, written by Kim E. Barett of the University of California, commends the findings of the Uppsala team, stating 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."
Vetenskapsr�det (The Swedish Research Council)
The editorial in the December issue of the prestigious journal Molecular Pharmacology, written by Kim E. Barett of the University of California, commends the findings of the Uppsala team, stating 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."
Vetenskapsr�det (The Swedish Research Council)
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