Human Intestinal Absorption

Human Intestinal Absorption

Human Intestinal Absorption (HIA) is the process through which orally administered drugs are absorbed from the intestine into the bloodstream.

Why is Human Intestinal Absorption Important?
The majority of high-value drugs on the market are orally administered and for an orally administered drug to be effective, it must be absorbed into the bloodstream. For this reason, a great deal of research has been carried out in attempts to predict human intestinal absorption (HIA) of compounds early in the drug discovery process. In vivo and in vitro models have been intensively used to estimate HIA, but these alternatives are costly, resource intensive and often difficult to interpret. Computational methods have been developed to overcome these hurdles and a classification model has been developed to identify compounds with good absorption based on a set of meaningful descriptors.

HIA Model
Percent Human Intestinal Absorption (%HIA) is defined as the percentage of orally administered drug reaching the hepatic portal vein. The Asteris HIA model is based on a dataset of over 250 compounds for which %HIA were reported in the literature. The model was then independently tested on 245 proprietary data points. The major drawback with the modelling data set is that it is highly biased towards well absorbed compounds. However, most of the available in silico models for HIA prediction are based on the same dataset.

By far the most common mechanism of absorption from the gastrointestinal tract is passive diffusion through the intestinal epithelial cells. This process depends heavily on the solute's ability to diffuse through the lipophilic phospholipids of the cellular membrane. In turn, the diffusion depends on the solvation/desolvation processes, on the surface interaction between solute and membrane, and on the H-bond potential of the solute. Based on this knowledge, descriptors representing properties (e.g. hydrogen bond donors, hydrogen bond acceptors and size of the molecule) that favour passive transport process through the membrane were selected.

The model for passive absorption across the intestinal wall provides either a '+' or '-' answer, indicating either >=30% passive absorption or <30% absorption respectively. The model had an overall classification rate of 96 % on the training set. Optimum results were obtained with 99% of '+' and 77% of '-' correctly predicted. The performance of this classifier against the independent test set resulted in 99% of '+' and 66% of '-' being correctly classified.

Observed vs Predicted HIA Category