Prediction and mechanistic interpretation of human oral drug absorption using MI-QSAR analysis
Resource
Molecular Pharmaceutics 4 (2): 218-231
Journal
Molecular Pharmaceutics
Journal Volume
4
Journal Issue
2
Pages
218-231
Date Issued
2007
Author(s)
Abstract
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 [R2 = 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, Q2 = 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. © 2007 American Chemical Society.
Subjects
Membrane barrier transport; MI-QSAR analysis; Oral drug absorption
SDGs
Other Subjects
adefovir; aminophenazone; amoxicillin; amphetamine; amrinone; atenolol; bornaprine; camazepam; captopril; cicaprost; cimetidine; codeine; corticosterone; diazepam; dihydrocodeine; disulfiram; ethambutol; famciclovir; famotidine; flecainide; lansoprazole; levodopa; methyldopa; naproxen; nisoldipine; nitrendipine; ouabain; oxprenolol; reproterol; unindexed drug; article; data analysis; drug absorption; drug diffusion; drug mechanism; drug research; drug solubility; drug structure; intestine absorption; molecular interaction; molecular weight; phospholipid membrane; priority journal; quantitative structure activity relation; Administration, Oral; Cell Membrane Permeability; Forecasting; Humans; Intestinal Absorption; Membranes, Artificial; Models, Molecular; Molecular Structure; Pharmaceutical Solutions; Phospholipids; Quantitative Structure-Activity Relationship
Type
journal article
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