ADME evaluation. 2. A computer model for the prediction of intestinal absorption in humans.
OBJECTIVE
To develop a computational method to rapidly evaluate human intestinal absorption, one of the drug properties included in the term ADME (Absorption, Distribution, Metabolism, Excretion). Poor ADME properties are the most important reason for drug failure in clinical development.


METHODS
The model developed is based on a modified contribution group method in which the basic parameters are structural descriptors identified by the CASE program, together with the number of hydrogen bond donors.


RESULTS
The human intestinal absorption model is a quantitative structure-activity relationship (QSAR) that includes 37 structural descriptors derived from the chemical structures of a data set containing 417 drugs. The model was able to predict the percentage of drug absorbed from the gastrointestinal tract with an r2 of 0.79 and a standard deviation of 12.32% of the compounds from the training set. The standard deviation for an external test set (50 drugs) was 12.34%.


CONCLUSIONS
The availability of reliable and fast models like the one we propose here to predict ADME/Tox properties could help speed up the process of finding compounds with improved properties, ultimately making the entire drug discovery process shorter and more cost efficient.
Klopman
Gilles
G
Department of Chemistry, Case Western Reserve University, 2074 Adelbert Road R205N, Cleveland, OH 44106, USA. gxk6@po.cwru.edu
Stefan
Liliana R
LR
Saiakhov
Roustem D
RD
D000327:Adsorption / Q000187:drug effects; D001682:Biological Availability; D003198:Computer Simulation / Q000706:statistics & numerical data*; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology*; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism; D011237:Predictive Value of Tests; D021281:Quantitative Structure-Activity Relationship
D004364:Pharmaceutical Preparations