title: Predicting phospholipidosis: a fluorescence noncell based in vitro assay for the determination of drug-phospholipid complex formation in early drug discovery.
abstract: This paper describes for the first time, a high-throughput fluorescence noncell based assay to screen for the drug-phospholipid interaction, which correlates to phospholipidosis. Anionic amphiphilic phospholipids can form complexes in aqueous solution, and its critical micelle concentration (CMC) can be determined using the fluorescence probe N,N-dimethyl-6-propionyl-2-naphthylamine (Prodan). Upon interaction with drug candidates, this CMC may shift to a lower value due to the association between lipids and drug candidates, the stronger the interaction, the greater the shift. Metabolism of a drug can change the degree of phospholipidosis depending on the rate of metabolism and the nature of the metabolite(s). Our data from 45 drugs and metabolites of 10 drugs using this fluorescence approach demonstrate a good correlation with phospholipidosis as reported with human studies, in vivo testing, and cellular assays. This assay therefore offers a fast, reliable, and cost-effective screening tool for early prediction of the phospholipidosis-inducing potential of drug candidates.
authors.affiliation: Chemical and Pharmaceutical Profiling, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States. LipingX.Zhou@Novartis.com
authors.forename: Liping
authors.initials: L
authors.lastname: Zhou
authors.forename: Gina
authors.initials: G
authors.lastname: Geraci
authors.forename: Sloan
authors.initials: S
authors.lastname: Hess
authors.forename: Linhong
authors.initials: L
authors.lastname: Yang
authors.forename: Jianling
authors.initials: J
authors.lastname: Wang
authors.forename: Upendra
authors.initials: U
authors.lastname: Argikar
mesh_terms: D015081:2-Naphthylamine / Q000031:analogs & derivatives / Q000737:chemistry; D004353:Drug Evaluation, Preclinical; D005456:Fluorescent Dyes / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008823:Micelles; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism*; D013050:Spectrometry, Fluorescence / Q000379:methods*
chemical_list: D005456:Fluorescent Dyes; D008823:Micelles; D004364:Pharmaceutical Preparations; D010743:Phospholipids; C038517:prodan; D015081:2-Naphthylamine