Relationships between structure and high-throughput screening permeability of diverse drugs with artificial membranes: Application to prediction of Caco-2 cell permeability

• Published in: Bioorganic & medicinal chemistry Vol. 13; no. 15; pp. 4721 - 4732
• Main Authors: Fujikawa, Masaaki, Ano, Rieko, Nakao, Kazuya, Shimizu, Ryo, Akamatsu, Miki
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01-08-2005; Elsevier Science
• Subjects: Artificial membrane permeability; Biological and medical sciences; Caco-2; Caco-2 Cells; Cell Membrane Permeability - drug effects; Drug Evaluation, Preclinical; General pharmacology; Humans; Medical sciences; Membranes, Artificial; Miscellaneous; PAMPA; Pharmacology. Drug treatments; Physicochemical properties. Structure-activity relationships; Quantitative Structure-Activity Relationship; Structure–property relationships; Testosterone - pharmacology; Artificial membrane permeability; PAMPA; Structure–property relationships; Caco-2; High throughput screening; Human; Drug; Statistical analysis; Prediction; Artificial membrane; Permeability; Modeling; PLS regression; Three dimensional model; Absorption; Cell line; Correlation analysis; Molecular model; Structure-property relationships; Property structure relationship; Colon; Chemometrics; Lipophilicity; Physicochemical properties
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2005.04.076

To evaluate the absorption of drugs with diverse structures across a membrane via the transcellular route, their permeability was measured by the parallel artificial membrane permeation assay (PAMPA). The permeability coefficients obtained by PAMPA were analyzed using a classical quantitative structure–activity relationship approach and 3D-QSAR, VolSurf. The permeability coefficients of the drugs were well correlated with the Caco-2 cell permeability.
To evaluate the absorption of drugs with diverse structures across a membrane via the transcellular route, their permeability was measured using the parallel artificial membrane permeation assay (PAMPA). The permeability coefficients obtained by PAMPA were analyzed using a classical quantitative structure–activity relationship (QSAR) approach with simple physicochemical parameters and 3D-QSAR, VolSurf. We formulated correlation equations for diverse drugs similar to the equation obtained for peptide-related compounds in our previous study. The hydrogen-bonding ability of molecules, not only the hydrogen-accepting ability but also the hydrogen-donating ability, in addition to hydrophobicity at a particular pH, was significant in determining variations in PAMPA permeability coefficients. Based on this result, an in silico good prediction model for the passive transcellular permeability of diverse structural compounds was obtained. The artificial lipid-membrane permeability coefficients of the drugs, except salicylic acid, were well correlated with the Caco-2 permeability in a previous report suggesting the importance of absorption by the transcellular mechanism for these drugs.