Experimental and theoretical predictions of intestinal drug absorption

Abstract: The subject of this thesis is the development of better experimental and computational predictions of the intestinal absorption properties of new drug candidates. In the last decade the drug discovery process has produced an increasing number of new drug candidates by the use of high throughput screening techniques. As a result, there is a demand for better screening methods also for biopharmaceutical properties such as oral drug absorption.The main objective was to develop computational methods to predict passive intestinal epithelial permeability from structural descriptors that take the three-dimensional shape of the molecules into consideration. Many molecular characteristics are influenced by conformational properties and intramolecular interactions. Few computational methods, however, take these factors adequately into consideration. Properties of the molecular surface are of special interest since the surface area is influenced by the three-dimensional shape of the molecule, and will determine how the compound is perceived by its surroundings.Initially, monolayers of human intestinal epithelial Caco-2 cells were confirmed to be a good in vitro model of the human intestinal epithelium in vivo for studies of passive transcellular drug transport. Thus, Caco-2 cell monolayers were concluded to be suitable for studies of relationships between the molecular structure of drugs and their ability to permeate the intestinal epithelium.A computational method based on the calculation of dynamic polar molecular surface area (PSAd) was developed for the prediction of intestinal epithelial drug absorption. The PSAd takes into consideration the three-dimensional shape and flexibility of the molecules. PSAd was found to better predict the intestinal epithelial permeability to drugs than more established computed predictors, e.g. the octanol/water partition coefficient and hydrogen bond-number, as well as newer experimental screening methods such as immobilised liposome chromatography. These results indicate that the hydrogen-bonding related descriptor PSAd is a promising new predictor of epithelial permeability.Although additional molecular properties, such as molecular charge, need to be included in a generally applicable method, PSAd or hydrogen bonding potential seems to be the dominating molecular property that determines the epithelial drug transport.