A doctoral thesis defended at the Institute of Chemistry of the University of Tartu has investigated the permeability of drug substances in the gastrointestinal tract using both experimental and cheminformatics methods. The results of the research improve our understanding of how the basic and acidic conditions of the gastrointestinal tract affect the permeability of drug substances.
One of the most significant characteristics of orally administered drugs (tablets, capsules and solutions) is absorption in the gastrointestinal tract, which depends on the solubility of the drug substance and its ability to pass through the wall of the gastrointestinal tract. Both solubility and permeability are affected by the pH of the environment, which varies from very acidic (in the stomach) to very basic (in the colon), and is dependent on whether the person has recently fed or fasted for some time. The pH of the gastrointestinal tract affects the characteristics of drug substances and sets the conditions under which, and in which region of the gastrointestinal tract, the drug substance can pass into the bloodstream.
“Thus far, permeability in the early stages of drug development has often been measured and described only in a neutral environment (pH = 7.4), but this results in inaccurate information about the permeability of drug substances in the gastrointestinal tract,” said Mare Oja, a junior research fellow at the Institute of Chemistry of the University of Tartu and author of the doctoral thesis.
During the investigation, the experimental membrane permeability of drug substances was measured at different pH values and a database was formed. Based on systematic data, calculation models have been developed that predict the membrane permeability of the drug substance, improve the selection of drug substance candidates at early stages of drug development and thus reduce attrition of drug substance candidates in later stages of drug development. “The developed models predicted permeability correctly 91% of the time, which shows how trustworthy they are,” said Oja.
According to the appointed opponent for the thesis, professor of chemistry Johann Gasteiger from Friedrich Alexander University in Germany, Oja’s experimental measurements have made it possible for the first time to obtain models that can be used to determine the dependency of membrane permeability on pH. He also considers it very valuable that the new models can be interpreted on a physical-chemical basis.
The supervisor of the thesis, senior research fellow Uko Maran from the Institute of Chemistry at the University of Tartu, said that the results of the research are wide-ranging and will help people understand absorption in the gastrointestinal tract. “The prediction models can be used directly in the early stages of drug development, but they allow for the assessment of the absorption of existing drug substances as well, if the pH of the gastrointestinal tract is known,” Maran explained.