Prediction and Mechanistic Interpretation of Human Oral Drug Absorption Using MI-QSAR Analysis

Membrane-interaction (MI)-QSAR analysis, which includes descriptors explicitly derived from simulations of solutes (drugs) interacting with phospholipid membrane models, was used to construct QSAR models for human oral intestinal drug absorption. A data set of 188 compounds, which are mainly drugs, was divided into a parent training set of 164 compounds and a test set of 24 compounds. Stable, but not highly fit (R 2 ) 0.68) MI-QSAR models could be built for all 188 compounds. However, the relatively large number (47) of drugs having 100% absorption, as well as all zwitterionic compounds (11), had to be eliminated from the training set in order to construct a linear five-term oral absorption diffusion model for 106 compounds which was both stable (R 2 ) 0.82, Q 2 ) 0.79) and predictive given the test set compounds were predicted with nearly the same average accuracy as the compounds of the training set. Intermolecular membrane-solute descriptors are essential to building good oral absorption models, and these intermolecular descriptors are displaced in model optimizations and intramolecular solute descriptors found in published oral absorption QSAR models. A general form for all of the oral intestinal absorption MI-QSAR models has three classes of descriptors indicative of three thermodynamic processes: (1) solubility and partitioning, (2) membrane- solute interactions, and (3) flexibility of the solute and/or membrane. The intestinal oral absorption MI-QSAR models were compared to MI-QSAR models previously developed for Caco-2 cell permeation and for blood-brain barrier penetration. The MI-QSAR models for all three of these ADME endpoints share several common descriptors, and suggest a common mechanism of transport across all three barriers. A further analysis of these three types of MI-QSAR models has been done to identify descriptor-term differences across these three models, and the corresponding differences in thermodynamic transport behavior of the three barriers.