title: Quantitative structure-permeability relationships at various pH values for acidic and basic drugs and drug-like compounds.
abstract: Absorption in gastrointestinal tract compartments varies and is largely influenced by pH. Therefore, considering pH in studies and analyses of membrane permeability provides an opportunity to gain a better understanding of the behaviour of compounds and to obtain good permeability estimates for prediction purposes. This study concentrates on relationships between the chemical structure and membrane permeability of acidic and basic drugs and drug-like compounds. The membrane permeability of 36 acidic and 61 basic compounds was measured using the parallel artificial membrane permeability assay (PAMPA) at pH 3, 5, 7.4 and 9. Descriptive and/or predictive single-parameter quantitative structure-permeability relationships were derived for all pH values. For acidic compounds, membrane permeability is mainly influenced by hydrogen bond donor properties, as revealed by models with r(2) > 0.8 for pH 3 and pH 5. For basic compounds, the best (r(2) > 0.7) structure-permeability relationships are obtained with the octanol-water distribution coefficient for pH 7.4 and pH 9, indicating the importance of partition properties. In addition to the validation set, the prediction quality of the developed models was tested with folic acid and astemizole, showing good matches between experimental and calculated membrane permeabilities at key pHs. Selected QSAR models are available at the QsarDB repository ( http://dx.doi.org/10.15152/QDB.166 ).
authors.affiliation: a Institute of Chemistry , University of Tartu , Ravila 14A, Tartu 50411 , Estonia.
authors.forename: M
authors.initials: M
authors.lastname: Oja
authors.affiliation: a Institute of Chemistry , University of Tartu , Ravila 14A, Tartu 50411 , Estonia.
authors.forename: U
authors.initials: U
authors.lastname: Maran
mesh_terms: D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption; D008567:Membranes, Artificial; D000442:Octanols / Q000737:chemistry; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D014867:Water / Q000737:chemistry
chemical_list: D008567:Membranes, Artificial; D000442:Octanols; D004364:Pharmaceutical Preparations; D014867:Water
keywords: PAMPA; QSAR; acidic drugs; basic drugs; membrane permeability; pH dependence