Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2485350 | Journal of Pharmaceutical Sciences | 2008 | 18 Pages |
Abstract
Measurement of permeation across a monolayer of the human adenocarcinoma cell line, Caco-2, is a popular surrogate for a compound's permeation across the human intestinal epithelium. Taken alone, however, Caco-2 permeability has certain limitations in the prediction of the extent of absorption of an orally-administered compound, because it does not take into account confounding factors such as solubility and dissolution in the gastrointestinal (GI) tract fluids. A simulation model is described that uses Caco-2 permeability measured in the apical to basolateral direction plus kinetic solubility in buffered solution (both measured at pH 7.4) to predict human intestinal absorption. The model features novel treatment of time-varying fluid volume in the GI tract, as a consequence of secretions into, and absorption of fluid from, the upper part of the GI tract. The model has been trained and cross-validated with data for 120 combinations of compound and dose. It has superior predictive power to recently published simulation and quantitative structure property relationship models, and is suitable for high-throughput screening during lead identification and lead optimisation in drug discovery.
Keywords
Related Topics
Health Sciences
Pharmacology, Toxicology and Pharmaceutical Science
Drug Discovery
Authors
Simon Thomas, Frances Brightman, Helen Gill, Sally Lee, Boris Pufong,