title: pH-gradient PAMPA-based in vitro model assay for drug-induced phospholipidosis in early stage of drug discovery.
abstract: In the present study we validated a widely used, high-throughput in vitro permeability model (PAMPA) to be used at the early stage of drug discovery for the phospholipidosis (PLD) prediction of drug-like compounds. Regarding the mechanism of action of PLD, our pH-gradient PAMPA system is the first noncell based model to mimic one-way transport of cationic amphiphilic drugs (CADs) from cytosol to the lysosome. Moreover, due to the fact that PLD can mainly occur in lung, liver, brain, kidney and heart, we have used similar commercially available original tissue-derived lipid fractions (heart, liver, brain), and in the case mimicking membrane of kidney and lung tissue we prepared tissue-mimetic artificial lipid mixtures in house. Metabolism of a drug can change the degree of PLD depending on the physicochemical properties of metabolites and the rate of metabolism. Our data from 57 drugs and 4 metabolites of earlier and 2 metabolites of newly recognized outliers (phenacetin and bupropion) using our pH-gradient PAMPA system show a good correlation with in vivo PLD data. Moreover, predictive ability of our best system, the lung specific pH-gradient PAMPA model was significantly better than widely used in silico models and it was also slightly better than that of the known noncell based models on our selection of compounds. Our pH-gradient PAMPA systems therefore offer mechanistically alternative, accurate and cost-effective screening tools for the early prediction of PLD potential of drug-like compounds.
authors: Compound Profiling Laboratory, Gedeon Richter Plc., Gyömrői út 19-21, Budapest H-1103, Hungary. Electronic address: gy.balogh@richter.hu.
authors: György T
authors: GT
authors: Balogh
authors: Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Budafoki út 9-11, Budapest H-1111, Hungary.
authors: Judit
authors: J
authors: Müller
authors: Compound Profiling Laboratory, Gedeon Richter Plc., Gyömrői út 19-21, Budapest H-1103, Hungary.
authors: Arpád
authors: A
authors: Könczöl
mesh_terms: D055808:Drug Discovery; D057166:High-Throughput Screening Assays; D006863:Hydrogen-Ion Concentration; D008954:Models, Biological; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism*
chemical_list: D004364:Pharmaceutical Preparations; D010743:Phospholipids