Use of the Distribution Coefficient in Brain Polar Lipids for the Assessment of Drug-Induced Phospholipidosis Risk

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 LogD_BPL assay (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 LogD_BPL parameter was first compared to the effective permeability in the parallel artificial membrane permeability assay (PAMPA), previously reported as correlating with PLD risk. Subsequently, the LogD_BPL for a set of 234 drugs with known PLD effect was measured, representing the largest data set of LogD_BPL data 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 LogD_BPL is an efficient descriptor to assess PLD risk, especially when corrected using the pK_a value of compounds, being superior to the distribution coefficient in octanol, LogD_OCT, and the effective permeability in the PAMPA assay. A multivariate statistical analysis approach was finally used to better define the intrinsic features of LogD_BPL, whose effect proved to be highly similar to that of volume of distribution in silico when used to predict brain distribution and PLD.