title: Phospholipidosis effect of drugs by adsorption into lipid monolayers.
abstract: Drug-induced phospholipidosis indicates an accumulation of phospholipids within lysosomes, which can occur during therapeutic treatment. Whether or not phospholipidosis represents a toxicological phenomenon is still under investigation, and in the last decade the Food and Drug Administration has been raising concerns about the possible consequences of this adverse event. Cationic amphiphilic drugs represent the majority of phospholipidosis inducers, followed by aminoglycoside and macrolide antibiotics. Although the mechanism of phospholipidosis induction is still uncertain, the interaction of drugs with phospholipids in the lysosomal membrane represents a key step. Therefore, the study of the drug/lipid complex formation will provide valuable insight into the causation of phospholipidosis at the molecular level and to identify the potential phospholipidosis risk associated with drug. In this study, we investigated the insertion profile of eleven drugs with known phospholipidosis effect into preformed Langmuir monolayers of various lipid compositions, to evaluate for the first time the drug/lipid interaction for phospholipidosis inducers and non-inducers in a dynamic approach. We found that the addition of dipalmitoylphosphatidylserine (DPPS) to dipalmitoylphosphatidylcholine (DPPC) to form the lipid monolayer allowed a clear identification of the phospholipidosis effect of the selected drugs based on the variation of the surface pressure, not only for cationic amphiphilic drugs but also for the aminoglycoside and the macrolide antiobiotics tested. Compared to a standard PAMPA assay, the new method appears to be more effective for the study of poorly soluble drugs.
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia, via Elce di Sotto 8, I-06123 Perugia, Italy. Electronic address: martina.ceccarelli@studenti.unipg.it.
authors.forename: Martina
authors.initials: M
authors.lastname: Ceccarelli
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia, via Elce di Sotto 8, I-06123 Perugia, Italy. Electronic address: raimondo.germani@unipg.it.
authors.forename: Raimondo
authors.initials: R
authors.lastname: Germani
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia, via del Liceo 1, I-06123 Perugia, Italy. Electronic address: serena.massari@unipg.it.
authors.forename: Serena
authors.initials: S
authors.lastname: Massari
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Quai Ernest-Ansermet 30, CH-1211 Geneva, Switzerland. Electronic address: charlotte.petit@unige.ch.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Petit
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Quai Ernest-Ansermet 30, CH-1211 Geneva, Switzerland.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Nurisso
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Quai Ernest-Ansermet 30, CH-1211 Geneva, Switzerland. Electronic address: jean-luc.wolfender@unige.ch.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Wolfender
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia, via Elce di Sotto 8, I-06123 Perugia, Italy. Electronic address: laura.goracci@unipg.it.
authors.forename: Laura
authors.initials: L
authors.lastname: Goracci
mesh_terms: D000327:Adsorption; D008064:Lipidoses / Q000139:chemically induced* / Q000378:metabolism; D008567:Membranes, Artificial; D010539:Permeability; D004364:Pharmaceutical Preparations; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism*; D013500:Surface Tension; D013696:Temperature
chemical_list: D008567:Membranes, Artificial; D004364:Pharmaceutical Preparations; D010743:Phospholipids
keywords: Cationic amphiphilic drugs; Drug insertion; Langmuir monolayers; PAMPA assay; Phospholipidosis