title: Use of the Distribution Coefficient in Brain Polar Lipids for the Assessment of Drug-Induced Phospholipidosis Risk.
abstract: In vitro safety assessment in early drug discovery represents an important step to detect potential safety-related liabilities. It reduces late stage attrition and allows candidate optimization. In this study, we report on the use of the LogDBPLassay (a recently published assay for the determination of drug distribution coefficients between an aqueous phase and porcine brain polar lipids extract) for phospholipidosis (PLD) risk evaluation. The LogDBPLparameter was first compared to the effective permeability in the parallel artificial membrane permeability assay (PAMPA), previously reported as correlating with PLD risk. Subsequently, the LogDBPLfor a set of 234 drugs with known PLD effect was measured, representing the largest data set of LogDBPLdata published so far, and the correlation with phospholipid accumulation was further investigated. In addition, a comparison with other in silico methods based on physicochemical parameters is reported. Results showed that LogDBPLis an efficient descriptor to assess PLD risk, especially when corrected using the pKavalue of compounds, being superior to the distribution coefficient in octanol, LogDOCT, and the effective permeability in the PAMPA assay. A multivariate statistical analysis approach was finally used to better define the intrinsic features of LogDBPL, whose effect proved to be highly similar to that of volume of distribution in silico when used to predict brain distribution and PLD.
authors.affiliation: Laboratory for Chemoinformatics and Molecular Modelling, Department of Chemistry, Biology and Biotechnology, University of Perugia , via Elce di Sotto 8, 06123 Perugia, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Ceccarelli
authors.affiliation: pRED, Pharma Research and Early Development, Pharmaceutical Research, Innovation Center Basel, F. Hoffmann-La Roche Ltd. , CH-4070 Basel, Switzerland.
authors.forename: B
authors.initials: B
authors.lastname: Wagner
authors.affiliation: pRED, Pharma Research and Early Development, Pharmaceutical Research, Innovation Center Basel, F. Hoffmann-La Roche Ltd. , CH-4070 Basel, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Alvarez-Sánchez
authors.affiliation: Laboratory for Chemoinformatics and Molecular Modelling, Department of Chemistry, Biology and Biotechnology, University of Perugia , via Elce di Sotto 8, 06123 Perugia, Italy.
authors.forename: G
authors.identifier: 0000-0002-4162-8692
authors.initials: G
authors.lastname: Cruciani
authors.affiliation: Laboratory for Chemoinformatics and Molecular Modelling, Department of Chemistry, Biology and Biotechnology, University of Perugia , via Elce di Sotto 8, 06123 Perugia, Italy.
authors.forename: L
authors.identifier: 0000-0002-9282-9013
authors.initials: L
authors.lastname: Goracci
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D064420:Drug-Related Side Effects and Adverse Reactions; D008064:Lipidoses / Q000139:chemically induced*; D004364:Pharmaceutical Preparations / Q000145:classification; D010743:Phospholipids / Q000378:metabolism*; D025341:Principal Component Analysis; D013552:Swine
chemical_list: D004364:Pharmaceutical Preparations; D010743:Phospholipids