Advertisement
Research Article| Volume 62, 100089, 2021

Inhibition of lysosomal phospholipase A2 predicts drug-induced phospholipidosis

Open AccessPublished:May 31, 2021DOI:https://doi.org/10.1016/j.jlr.2021.100089
Inhibition of lysosomal phospholipase A2 predicts drug-induced phospholipidosis
Previous ArticleThe role of full-length apoE in clearance of Gram-negative bacteria and their endotoxins
Next ArticleAtherosclerosis-associated hepatic secretion of VLDL but not PCSK9 is dependent on cargo receptor protein Surf4

      Abstract

      Phospholipidosis, the excessive accumulation of phospholipids within lysosomes, is a pathological response observed following exposure to many drugs across multiple therapeutic groups. A clear mechanistic understanding of the causes and implications of this form of drug toxicity has remained elusive. We previously reported the discovery and characterization of a lysosome-specific phospholipase A2 (PLA2G15) and later reported that amiodarone, a known cause of drug-induced phospholipidosis, inhibits this enzyme. Here, we assayed a library of 163 drugs for inhibition of PLA2G15 to determine whether this phospholipase was the cellular target for therapeutics other than amiodarone that cause phospholipidosis. We observed that 144 compounds inhibited PLA2G15 activity. Thirty-six compounds not previously reported to cause phospholipidosis inhibited PLA2G15 with IC50 values less than 1 mM and were confirmed to cause phospholipidosis in an in vitro assay. Within this group, fosinopril was the most potent inhibitor (IC50 0.18 μM). Additional characterization of the inhibition of PLA2G15 by fosinopril was consistent with interference of PLA2G15 binding to liposomes. PLA2G15 inhibition was more accurate in predicting phospholipidosis compared with in silico models based on pKa and ClogP, measures of protonation, and transport-independent distribution in the lysosome, respectively. In summary, PLA2G15 is a primary target for cationic amphiphilic drugs that cause phospholipidosis, and PLA2G15 inhibition by cationic amphiphilic compounds provides a potentially robust screening platform for potential toxicity during drug development.

      Supplementary key words

      Abbreviations:

      CAD (cationic amphiphilic drug), DIP (drug-induced phospholipidosis), DODPC (1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine), DOPC (1,2-dioleoyl-palmitoyl-sn-glycero-3-phosphocholine), HPTLC (high-performance thin layer chromatography), LPLA2 (lysosomal phospholipase A2), NAS (N-acetyl-sphingosine), pNPB (p-nitro-phenyl butyrate)
      Phospholipidosis is the excess storage of phospholipids within lysosomes. Drug-induced phospholipidosis (DIP), in distinction to inherited forms of lysosomal phospholipid accumulation such as those associated with disorders such as Niemann–Pick C disease, represents an acquired lysosomal disorder (
      • Anderson N.
      • Borlak J.
      Drug-induced phospholipidosis.
      FEBS Lett. 2006; 580: 5533-5540
      ,
      • Shayman J.A.
      • Abe A.
      Drug induced phospholipidosis: an acquired lysosomal storage disorder.
      Biochim. Biophys. Acta. 2013; 1831: 602-611
      ). DIP most often involves the lung, liver, or kidney where it is associated with pulmonary fibrosis, hepatic steatosis or steatohepatitis, and acute or chronic kidney injury, respectively. Phospholipidosis often, but not always, results from exposure to basic cationic amphiphilic drugs (CADs). DIP is measured experimentally by use of in vitro or in vivo assays and is often observed in clinical settings. It is among the most common forms of drug toxicity as it is associated with exposure to more than 50 FDA-approved agents. When DIP is detected in preclinical screening studies, an otherwise promising compound may be abandoned. If DIP is found in patients under treatment with a specific drug, then the therapeutic is often discontinued. Research on DIP has been dominated by three overarching questions. First, what are the mechanisms responsible for DIP? Second, what chemical properties of a candidate compound can be used to predict phospholipidosis and used as a guide for further development? Third, what significant short- and long-term toxicities are the specific consequences of DIP?
      With regard to the first question, several mechanisms have been proposed as the basis DIP. These include the stimulation of phospholipid synthesis (
      • Chen G.L.
      • Sutrina S.L.
      • Frayer K.L.
      • Chen W.W.
      Effects of lysosomotropic agents on lipogenesis.
      Arch. Biochem. Biophys. 1986; 245: 66-75
      ), the direct binding of CADs to lysosomal phospholipases with inhibition of these enzymes by competitive or allosteric mechanisms (
      • Kubo M.
      • Hostetler K.Y.
      Mechanism of cationic amphiphilic drug inhibition of purified lysosomal phospholipase A1.
      Biochemistry. 1985; 24: 6515-6520
      ), the inhibition of lysosomal trafficking to lysosomes (
      • Ikeda K.
      • Hirayama M.
      • Hirota Y.
      • Asa E.
      • Seki J.
      • Tanaka Y.
      Drug-induced phospholipidosis is caused by blockade of mannose 6-phosphate receptor-mediated targeting of lysosomal enzymes.
      Biochem. Biophys. Res. Commun. 2008; 377: 268-274
      ), the displacement of phospholipases from the lysosomal membrane with secondary degradation by lysosomal proteases (
      • Hurwitz R.
      • Ferlinz K.
      • Sandhoff K.
      The tricyclic antidepressant desipramine causes proteolytic degradation of lysosomal sphingomyelinase in human fibroblasts.
      Biol. Chem. Hoppe Seyler. 1994; 375: 447-450
      ), and the binding of CADs to phospholipids with prevention of their degradation (
      • Joshi U.M.
      • Kodavanti P.R.
      • Coudert B.
      • Dwyer T.M.
      • Mehendale H.M.
      Types of interaction of amphiphilic drugs with phospholipid vesicles.
      J. Pharmacol. Exp. Ther. 1988; 246: 150-157
      ). Lysosomal phospholipase A1, A2, and C activities have been previously associated with DIP. However, to date only three phospholipases are known to be lysosome-based. They include acid sphingomyelinase (
      • Henry B.
      • Ziobro R.
      • Becker K.A.
      • Kolesnick R.
      • Gulbins E.
      Acid sphingomyelinase.
      Handb. Exp. Pharmacol. 2013; : 77-88
      ), phospholipase D3 (
      • Gonzalez A.C.
      • Schweizer M.
      • Jagdmann S.
      • Bernreuther C.
      • Reinheckel T.
      • Saftig P.
      • Damme M.
      Unconventional trafficking of mammalian phospholipase D3 to lysosomes.
      Cell Rep. 2018; 22: 1040-1053
      ), and lysosomal phospholipase A2 (
      • Shayman J.A.
      • Tesmer J.J.G.
      Lysosomal phospholipase A2.
      Biochim. Biophys. Acta Mol. Cell Biol. Lipids. 2019; 1864: 932-940
      ).
      With regard to the second question, efforts to predict DIP have generally followed two strategies. The first approach has employed analyses in which the physical properties of drugs are correlated with empirically observed phospholipidosis (
      • Pelletier D.J.
      • Gehlhaar D.
      • Tilloy-Ellul A.
      • Johnson T.O.
      • Greene N.
      Evaluation of a published in silico model and construction of a novel Bayesian model for predicting phospholipidosis inducing potential.
      J. Chem. Inf. Model. 2007; 47: 1196-1205
      ,
      • Kruhlak N.L.
      • Choi S.S.
      • Contrera J.F.
      • Weaver J.L.
      • Willard J.M.
      • Hastings K.L.
      • Sancilio L.F.
      Development of a phospholipidosis database and predictive quantitative structure-activity relationship (QSAR) models.
      Toxicol. Mech. Methods. 2008; 18: 217-227
      ,
      • Orogo A.M.
      • Choi S.S.
      • Minnier B.L.
      • Kruhlak N.L.
      Construction and consensus performance of (Q)sar models for predicting phospholipidosis using a dataset of 743 compounds.
      Mol. Inform. 2012; 31: 725-739
      ,
      • Choi S.S.
      • Kim J.S.
      • Valerio Jr., L.G.
      • Sadrieh N.
      In silico modeling to predict drug-induced phospholipidosis.
      Toxicol. Appl. Pharmacol. 2013; 269: 195-204
      ). The second strategy has used the development of novel in vitro assays that can be applied to the screening of individual drug candidates or chemical libraries to predict phospholipidosis potential. These assays include those that detect lipid accumulation in cell lines or that specifically measure lysosome associated lipid biomarkers such as bis(monoacylglycerol)phosphate (
      • Tengstrand E.A.
      • Miwa G.T.
      • Hsieh F.Y.
      Bis(monoacylglycerol)phosphate as a non-invasive biomarker to monitor the onset and time-course of phospholipidosis with drug-induced toxicities.
      Expert Opin. Drug Metab. Toxicol. 2010; 6: 555-570
      ) or gene expression profiling (
      • Sawada H.
      • Takami K.
      • Asahi S.
      A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system.
      Toxicol. Sci. 2005; 83: 282-292
      ). The assessment of these various in silico and in vitro strategies is limited by the absence of proof of a mechanism responsible for DIP.
      With regard to the third question, a determination of the pathological significance of phospholipidosis has been limited by the lack of identification and characterization of a specific target or targets of compounds that cause DIP. Identifying the cellular target or targets responsible for DIP as distinguished from toxicities resulting from separate off-target effects would represent a significant step in understanding and managing this form of drug toxicity.
      Our group identified an enzyme with 1-O-acyl-ceramide synthase activity and subsequently characterized a purified enzyme as lysosomal phospholipase A2 (LPLA2), now designated PLA2G15 (
      • Abe A.
      • Shayman J.A.
      • Radin N.S.
      A novel enzyme that catalyzes the esterification of N-acetylsphingosine. Metabolism of C2-ceramides.
      J. Biol. Chem. 1996; 271: 14383-14389
      ,
      • Abe A.
      • Shayman J.A.
      Purification and characterization of 1-O-acylceramide synthase, a novel phospholipase A2 with transacylase activity.
      J. Biol. Chem. 1998; 273: 8467-8474
      ,
      • Hiraoka M.
      • Abe A.
      • Shayman J.A.
      Cloning and characterization of a lysosomal phospholipase A2, 1-O-acylceramide synthase.
      J. Biol. Chem. 2002; 277: 10090-10099
      ). LPLA2 has an acidic pH optimum and colocalizes with lysosomes and late endosomes. Loss of function of LPLA2 in mice results in alveolar macrophage foam cell formation and surfactant accumulation, a phenotype similar to that observed with amiodarone-associated phospholipidosis (
      • Hiraoka M.
      • Abe A.
      • Lu Y.
      • Yang K.
      • Han X.
      • Gross R.W.
      • Shayman
      Lysosomal phospholipase A2 and phospholipidosis.
      Mol. Cell Biol. 2006; 26: 6139-6148
      ). In subsequent work we reported that amiodarone is a potent inhibitor of LPLA2, but does so by inhibition of electrostatic charge interactions between the hydrolase and anionic phospholipids (
      • Abe A.
      • Hiraoka M.
      • Shayman J.A.
      A role for lysosomal phospholipase A2 in drug induced phospholipidosis.
      Drug Metab. Lett. 2007; 1: 49-53
      ). This mechanism of action was further substantiated by our determination of the crystal structure of LPLA2 and the identification of critical residues in the lipid membrane-binding domain (
      • Glukhova A.
      • Hinkovska-Galcheva V.
      • Kelly R.
      • Abe A.
      • Shayman J.A.
      • Tesmer J.J.
      Structure and function of lysosomal phospholipase A2 and lecithin:cholesterol acyltransferase.
      Nat. Commun. 2015; 6: 6250
      ).
      Based on these studies we considered whether the inhibition of LPLA2 by cationic amphiphilic compounds is a more general mechanism for DIP. We assayed two libraries of small molecules for their ability to inhibit LPLA2 and correlate this inhibition with physical properties of these compounds used by others as the basis for predictive models of phospholipidosis. The first library consisted of drugs known to cause phospholipidosis in either in vitro or in vivo studies based on published reports. The second library consisted of compounds for which DIP has not been previously reported. We observed that inhibition of LPLA2 strongly correlates with drugs reported to cause phospholipidosis and have identified drugs that have not previously known to cause phospholipidosis, not all of which are cationic amphiphiles.

      Materials and Methods

      Materials

      1,2-dioleoyl-palmitoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (DODPC), and brain porcine sulfatide ammonium salt were purchased from Avanti Polar Lipids (Birmingham, AL). p-Nitro-phenyl butyrate (pNPB) was from Sigma (St. Louis, MO). Purified recombinant mouse LPLA2 was produced by Proteos Inc. (Kalamazoo, MI) as previously reported (
      • Glukhova A.
      • Hinkovska-Galcheva V.
      • Kelly R.
      • Abe A.
      • Shayman J.A.
      • Tesmer J.J.
      Structure and function of lysosomal phospholipase A2 and lecithin:cholesterol acyltransferase.
      Nat. Commun. 2015; 6: 6250
      ). High-performance thin layer chromatography (HPTLC) silica gel plates (10 × 20 cm) were from Merck KG@A (Darmstadt, Germany). All cationic amphiphilic drugs and controls used in this study were obtained from Sigma-Aldrich (St. Louis, MO) with the following exceptions ay-9944 and suramin from Calbiochem (San Diego, CA), and clenbuterol and yohimbine were from Cayman Chemicals (Ann Arbor, MI).

      Transacylase activity of LPLA2

      The LPLA2 activity assay is based on the following principles (
      • Shayman J.A.
      • Abe A.
      1-O-acylceramide synthase.
      Methods Enzymol. 2000; 311: 105-117
      ). LPLA2 is uniquely characterized as having an acidic pH optimum and as a transacylase recognizing short-chain lipophilic alcohols as acceptors. Based on these properties, short-chain 1-O-acyl-ceramides are unique products of this reaction. Because LPLA2 binds preferentially to negatively charged liposomes, sulfatide was included in the liposomes but is not itself a substrate and does not function as a cofactor for lysosomal hydrolases. The transacylase reaction is based on the unique property of LPLA2 to transfer an acyl group from the sn-2 or sn-1 position of a glycerophospholipid to N-acetyl-sphingosine (NAS) forming 1-O-acyl-N-acetylsphingoine (1-O-acyl-NAS) (
      • Abe A.
      • Shayman J.A.
      Purification and characterization of 1-O-acylceramide synthase, a novel phospholipase A2 with transacylase activity.
      J. Biol. Chem. 1998; 273: 8467-8474
      ,
      • Glukhova A.
      • Hinkovska-Galcheva V.
      • Kelly R.
      • Abe A.
      • Shayman J.A.
      • Tesmer J.J.
      Structure and function of lysosomal phospholipase A2 and lecithin:cholesterol acyltransferase.
      Nat. Commun. 2015; 6: 6250
      ,
      • Hinkovska-Galcheva V.
      • Kelly R.
      • Manthei K.A.
      • Bouley R.
      • Yuan W.
      • Schwendeman A.
      • Tesmer J.J.G.
      • Shayman1 J.A.
      Determinants of pH profile and acyl chain selectivity in lysosomal phospholipase A2.
      J. Lipid Res. 2018; 59: 1205-1218
      ). 1-O-acyl-NAS is not known to be a product of any other enzyme. The reaction mixture included 50 mM sodium citrate buffer (pH 4.5), 10 μg/ml bovine serum albumin, and liposomes consisting of 38 μM N-acetyl-sphingosine, 127 μM DOPC, 12.7 μM sulfatide, and test compound in a total volume of 0.5 ml. The test compounds were dissolved in DMSO. The final DMSO concentration in the reaction mixture was 0.125%. The reaction was initiated by the addition of recombinant LPLA2 protein (30 ng) and carried out at 37 ˚C for 10 min. The reaction was terminated by the addition of 3 ml chloroform/methanol (2/1, v/v), followed by 0.3 ml of 9% (w/v) NaCl. After centrifugation for 7 min at 1800 × g, the resulting lower layer was transferred to new tube and dried under stream of nitrogen gas. The dried lipid was dissolved in 40 μl of chloroform/methanol (2/1, v/v) and applied to HPTLC plates. HPTLC plates were run in chloroform/acetic acid (9/1, v/v). The plates were dried and soaked in 8% (w/v) CuSO4.5H2O, 6.8% (v/v) H3PO4, and 32% (v/v) methanol and then charred for 15 min in an oven at 150 ˚C. Scanned plates were analyzed by NIH ImageJ 1.651j8 (National Institutes of Health).

      LPLA2 esterase assay

      pNPB was used to directly measure the activity of LPLA2. pNPB is a water-soluble substrate that can directly access the catalytic site in the absence of liposomes (
      • Abe A.
      • Shayman J.A.
      The role of negatively charged lipids in lysosomal phospholipase A2 function.
      J. Lipid Res. 2009; 50: 2027-2035
      ). A reaction mixture of pNPB (0.2 mM) and cationic amphiphilic compounds at varying concentrations in sodium citrate buffer (pH 4.5) was prepared and prewarmed to 37°C for 5 min in a total volume of 500 μl. The reaction was initiated by the addition of recombinant LPLA2 (5 μg). At predetermined times, 120 μl of the reaction mixture was transferred to a tube containing 120 μl of 0.2 M NaHCO3 and kept on ice. The cold reaction product was subsequently warmed to 37°C, and the absorbance of the reaction product, p-nitrophenoxide, was measured at 400 nm with a Beckman Du-640 spectrophotometer.

      Liposome LPLA2 cosedimentation assay

      Liposomes consisting of DOPC and sulfatide (10:1 M ratio, 127 μM total lipid) were incubated with 5 μg of LPLA2 in 500 μl 50 mM sodium citrate, at pH 4.5 for 30 min on ice. The reaction mixture was then centrifuged for 1 h at 150,000 g at 4°C. The resulting precipitate was rinsed with cold 50 mM sodium citrate pH 4.5 and dissolved with 40 μl of SDS-PAGE sample buffer. The sample was separated by using 10% SDS-PAGE. After electrophoresis, LPLA2 was detected with Coomassie brilliant blue. Band quantification was performed with ImageJ software I1.651j8 (
      • Abe A.
      • Shayman J.A.
      The role of negatively charged lipids in lysosomal phospholipase A2 function.
      J. Lipid Res. 2009; 50: 2027-2035
      ).

      LPLA2 thermal stability measurement

      A thermal stability assay was employed to determine the melting point (Tm) of LPLA2 (
      • Semisotnov G.V.
      • Rodionova N.A.
      • Razgulyaev O.I.
      • Uversky V.N.
      • Gripas A.F.
      • Gilmanshin R.I.
      Study of the "molten globule" intermediate state in protein folding by a hydrophobic fluorescent probe.
      Biopolymers. 1991; 31: 119-128
      ). An incubation mixture consisting of 2.5 μl of 8x SYPRO Orange, 1 μg of LPLA2 in 50 mM Na citrate at pH 4.5, and ddH2O in a final volume of 20 μl was added to wells of a 48-well thin-wall PCR plate. The plates were sealed with Optical-Quality Sealing Tape (Bio-Rad) and heated in a Real-Time PCR Detection System Life Technology (Thermo Fisher, Ann Arbor, MI) from 20 to 90°C in steps of 0.2°C. Tm values were calculated as the inflection point of the melting curve using the instrument software.

      Screening phospholipidosis assay

      The assay was modified from one reported previously (
      • Nioi P.
      • Perry B.K.
      • Wang E.J.
      • Gu Y.Z.
      • Snyder R.D.
      In vitro detection of drug-induced phospholipidosis using gene expression and fluorescent phospholipid based methodologies.
      Toxicol. Sci. 2007; 99: 162-173
      ). MDCK cells were seeded in 100 μl culture medium at cell density 3,000 cells per well in 96-well black-walled clear bottom Greiner micro plates (Sigma-Aldrich) and were allowed to adhere overnight. Cell culture medium was replaced with phospholipidosis staining solution (1:1,000 dilution) of LipidTOX Red Phospholipidosis detection reagent (Invitrogen), and simultaneously with different concentrations of fosinopril or amiodarone in total volume of 100 μl. Compounds were prepared as stock solutions at 200-fold higher concentration than the desired top concentration (solvent concentration maintained at 0.5%). Compound treatment was performed for 24 h with 5% CO2 at 37°C. Then the culture medium was removed and cells were fixed with 100 μl, fixation solution consisting of 4% formaldehyde in phosphate buffered saline (PBS). After washing, cells were incubated with 1 drop of NucBlue Live (NBL) for 20 min. Cells were washed three times with PBS, and fluorescence image acquisition was performed using the Molecular Devices (San Jose, CA) spectrophotometer. Cell nuclei fluorescence was detected using a 410–480 nm emission filter, red phospholipidosis detection was performed using 549–615 nm emission filter.

      Image acquisition and processing

      Ninety six-well plates were visualized under a Leica DM IRB microscope and images acquired with an Olympus DP70 camera via Olympus DP Manager software. All images were identically adjusted in GNU Image Manipulation Program to improve background and overall image clarity postacquisition.

      LipidTOX red particle quantification

      Images were quantified utilizing ImageJ as follows. Images were initially processed with the Subtract Background feature with a rolling ball radius of 50 pixels. Following conversion to 8 bit, images were subjected to Auto Local Threshold processing using the Bernsen algorithm with a radius of 15. Particles were subsequently quantified and analyzed utilizing the Analyze Particle feature. A total of six 10x fields (2 per triplicate) were quantified with an average of over 4,000 cells per field.

      Statistical analysis

      Data from at least three independent experiments were analyzed with a paired t test in GraphPad Prism 7 and expressed as mean ± SD. The differences between control and treated samples were considered statistically significant at P < 0.05.

      Results

      A library of 163 compounds was assembled and assayed for inhibition of LPLA2. One hundred and nine compounds were identified via literature review as causing phospholipidosis based on either in vitro or in vivo assays (Table 1). In the latter case, the animal species employed is indicated. These compounds were chosen represent a wide spectrum of therapeutic indications, having a range of pKa and ClogP that fell within and outside of values commonly associated with DIP and in which the lysosomal pathology is observed across a range of organs. Most, but not all, of the compounds are cationic amphiphiles, and several are central nervous system penetrant. A second set of 54 compounds was assayed representing drugs for which no reports of phospholipidosis were found but which were representative of a similar spectrum of chemical properties (Table 2). Included in this set were metabolites chosen as negative controls (glucose, leucine, and uridine). The primary clinical indications listed in these tables are consistent with a wide range of cellular targets for these compounds.
      Table 1Test compounds reported to cause phospholipidosis
      Generic nameUPAC DesignationCAS NumberIndicationClogPpKa (basic)Ploemen ValuePred PloemenPred modified PloemenLPLA2 IC50 (μM)In Vitro PLDIn Vivo PLDRefs
      Alprenolol1-(o-allylphenoxy)-3-(isopropylamino)-2-propanol13707-88-5Antihypertensive, antiarrhythmic, sympatholytic agent3.19.67103++172.7Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Treyer A.
      • Mateus A.
      • Wisniewski J.R.
      • Boriss H.
      • Matsson P.
      • Artursson P.
      Intracellular drug bioavailability: effect of neutral lipids and phospholipids.
      Mol. Pharm. 2018; 15: 2224-2233
      )
      Alverineethyl bis (3-phenylpropyl)amine150-59-4Antidiarrheal5.7310.44142++40.01Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Kornhuber J.
      • Muehlbacher M.
      • Trapp S.
      • Pechmann S.
      • Friedl A.
      • Reichel M.
      • Mühle C.
      • Terfloth L.
      • Groemer T.W.
      • Spitzer G.M.
      • Liedl K.R.
      • Gulbins E.
      • Tripal P.
      Identification of novel functional inhibitors of acid sphingomyelinase.
      PLoS One. 2011; 6e23852
      )
      Ambroxol2-amino-3,5-dibromo-N-(trans-4-hydroxycyclohexyl) benzylamine28828-92-4Mucolytic3.729.0195++59Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Heath M.F.
      • Jacobson W.
      The inhibition of lysosomal phospholipase A from rabbit lung by ambroxol and its consequences for pulmonary surfactant.
      Lung. 1985; 163: 337-344
      )
      Amiodarone{2-[4-(2-butyl-1-benzofuran-3-carbonyl)-2,6-diiodophenoxy] ethyl} diethyl amine1951-25-3Antiarrhythmic7.578.47130++8.3YesH,R(
      • Sawada H.
      • Takami K.
      • Asahi S.
      A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system.
      Toxicol. Sci. 2005; 83: 282-292
      ,
      • Abe A.
      • Shayman J.A.
      The role of negatively charged lipids in lysosomal phospholipase A2 function.
      J. Lipid Res. 2009; 50: 2027-2035
      ,
      • Nioi P.
      • Perry B.K.
      • Wang E.J.
      • Gu Y.Z.
      • Snyder R.D.
      In vitro detection of drug-induced phospholipidosis using gene expression and fluorescent phospholipid based methodologies.
      Toxicol. Sci. 2007; 99: 162-173
      ,
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Lenhard S.C.
      • Lev M.
      • Webster L.O.
      • Peterson R.A.
      • Goulbourne C.N.
      • Miller R.T.
      • Jucker B.M.
      Hepatic phospholipidosis is associated with altered hepatobiliary function as assessed by gadoxetate dynamic contrast-enhanced magnetic resonance imaging.
      Toxicol. Pathol. 2016; 44: 51-60
      ,
      • Gonzalez-Rothi R.J.
      • Hannan S.E.
      • Hood C.I.
      • Franzini D.A.
      Amiodarone pulmonary toxicity presenting as bilateral exudative pleural effusions.
      Chest. 1987; 92: 179-182
      ,
      • Fischer H.
      • Atzpodien E.A.
      • Csato M.
      • Doessegger L.
      • Lenz B.
      • Schmitt G.
      • Singer T.
      In silico assay for assessing phospholipidosis potential of small druglike molecules: training, validation, and refinement using several data sets.
      J. Med. Chem. 2012; 55: 126-139
      ,
      • Morelli J.K.
      • Buehrle M.
      • Pognan F.
      • Barone L.R.
      • Fieles W.
      • Ciaccio P.J.
      Validation of an in vitro screen for phospholipidosis using a high-content biology platform.
      Cell Biol. Toxicol. 2006; 22: 15-27
      ,
      • Hanumegowda U.M.
      • Wenke G.
      • Regueiro-Ren A.
      • Yordanova R.
      • Corradi J.P.
      • Adams S.P.
      Phospholipidosis as a function of basicity, lipophilicity, and volume of distribution of compounds.
      Chem. Res. Toxicol. 2010; 23: 749-755
      ,
      • Shahane S.A.
      • Huang R.
      • Gerhold D.
      • Baxa U.
      • Austin C.P.
      • Xia M.
      Detection of phospholipidosis induction: a cell-based assay in high-throughput and high-content format.
      J. Biomol. Screen. 2014; 19: 66-76
      ,
      • Tochitani T.
      • Yamashita A.
      • Kouchi M.
      • Fujii Y.
      • Matsumoto I.
      • Miyawaki I.
      • Yamada T.
      • Funabashi H.
      Changes in plasma concentrations of corticosterone and its precursors after ketoconazole administration in rats: An application of simultaneous measurement of multiple steroids using LC-MS/MS.
      Exp. Toxicol. Pathol. 2016; 68: 125-131
      )
      Amitriptylinedimethyl(3-{tricyclo[9.4.0.03,8]pentadeca-1(15),3,5,7,11,13-hexaen-2-ylidene}propyl)amine50-48-6Antidepressant5.19.76121++14.7YesR(
      • Pelletier D.J.
      • Gehlhaar D.
      • Tilloy-Ellul A.
      • Johnson T.O.
      • Greene N.
      Evaluation of a published in silico model and construction of a novel Bayesian model for predicting phospholipidosis inducing potential.
      J. Chem. Inf. Model. 2007; 47: 1196-1205
      ,
      • Sawada H.
      • Takami K.
      • Asahi S.
      A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system.
      Toxicol. Sci. 2005; 83: 282-292
      ,
      • Nioi P.
      • Perry B.K.
      • Wang E.J.
      • Gu Y.Z.
      • Snyder R.D.
      In vitro detection of drug-induced phospholipidosis using gene expression and fluorescent phospholipid based methodologies.
      Toxicol. Sci. 2007; 99: 162-173
      ,
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Morelli J.K.
      • Buehrle M.
      • Pognan F.
      • Barone L.R.
      • Fieles W.
      • Ciaccio P.J.
      Validation of an in vitro screen for phospholipidosis using a high-content biology platform.
      Cell Biol. Toxicol. 2006; 22: 15-27
      ,
      • Hanumegowda U.M.
      • Wenke G.
      • Regueiro-Ren A.
      • Yordanova R.
      • Corradi J.P.
      • Adams S.P.
      Phospholipidosis as a function of basicity, lipophilicity, and volume of distribution of compounds.
      Chem. Res. Toxicol. 2010; 23: 749-755
      ,
      • Atienzar F.
      • Gerets H.
      • Dufrane S.
      • Tilmant K.
      • Cornet M.
      • Dhalluin S.
      • Ruty B.
      • Rose G.
      • Canning M.
      Determination of phospholipidosis potential based on gene expression analysis in HepG2 cells.
      Toxicol. Sci. 2007; 96: 101-114
      ,
      • Przybylak K.R.
      • Cronin M.T.
      In silico studies of the relationship between chemical structure and drug induced phospholipidosis.
      Mol. Inform. 2011; 30: 415-429
      )
      Amorolfine2R,6S-2,6-dimethyl-4-(2-{[4-(2-methylbutan-2-yl) phenyl] methyl}propyl)morpholine78613-35-1Antifungal5.628.49104++41.47Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Kornhuber J.
      • Muehlbacher M.
      • Trapp S.
      • Pechmann S.
      • Friedl A.
      • Reichel M.
      • Mühle C.
      • Terfloth L.
      • Groemer T.W.
      • Spitzer G.M.
      • Liedl K.R.
      • Gulbins E.
      • Tripal P.
      Identification of novel functional inhibitors of acid sphingomyelinase.
      PLoS One. 2011; 6e23852
      )
      Anastrozole2;2″-[5-(1H-1;2;4-Triazol-1-ylmethyl)-1,3-phenylene]bis(2-methyl-propiononitrile)120511-73-1Chemotherapy2.3129.3--4.82Yes(
      • Zapata E.
      • Zubiaurre L.
      • Bujanda L.
      • Pierola A.
      Anastrozole-induced hepatotoxicity.
      Eur. J. Gastroenterol. Hepatol. 2006; 18: 1233-1234
      ,
      • Hozumi Y.
      • Suemasu K.
      • Takei H.
      • Aihara T.
      • Takehara M.
      • Saito T.
      • Ohsumi S.
      • Masuda N.
      • Ohashi Y.
      The effect of exemestane, anastrozole, and tamoxifen on lipid profiles in Japanese postmenopausal early breast cancer patients: final results of National Surgical Adjuvant Study BC 04, the TEAM Japan sub-study.
      Ann. Oncol. 2011; 22: 1777-1782
      )
      Astemizole1-(4-fluorobenzyl)-2-(1-[4-methoxyphenethyl]piperidin-4-yl)aminobenzimidazole68844-77-9Antihistamine5.928.75112++8.19Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Gonzalez-Rothi R.J.
      • Hannan S.E.
      • Hood C.I.
      • Franzini D.A.
      Amiodarone pulmonary toxicity presenting as bilateral exudative pleural effusions.
      Chest. 1987; 92: 179-182
      ,
      • Przybylak K.R.
      • Cronin M.T.
      In silico studies of the relationship between chemical structure and drug induced phospholipidosis.
      Mol. Inform. 2011; 30: 415-429
      )
      ay-9944trans-1,4- bis(2-chlorobenzylaminomethyl)

      cyclohexane      		366-93-8Hypocholestrol-emic6.49.1124-+116YesR,Ra, M(
      • Sawada H.
      • Takami K.
      • Asahi S.
      A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system.
      Toxicol. Sci. 2005; 83: 282-292
      ,
      • Yoshida Y.
      • Arimoto K.
      • Sato M.
      • Sakuragawa N.
      • Arima M.
      • Satoyoshi E.
      Reduction of acid sphingomyelinase activity in human fibroblasts induced by AY-9944 and other cationic amphiphilic drugs.
      J. Biochem. 1985; 98: 1669-1679
      ,
      • Halliwell W.H.
      Cationic amphiphilic drug-induced phospholipidosis.
      Toxicol. Pathol. 1997; 25: 53-60
      ,
      • Kikkawa Y.
      • Motoyama E.K.
      Effect of AY-9944, a cholesterol biosynthesis inhibitor, on fetal lung development and on the development of type II alveolar epithelial cells.
      Lab. Invest. 1973; 28: 48-54
      ,
      • Rawlins F.A.
      • Uzman B.G.
      Effect of AY-9944, a cholesterol biosynthesis inhibitor, on peripheral nerve myelination.
      Lab. Invest. 1970; 23: 184-189
      )
      Benzbromarone2,6-dibromo-4-(2-ethyl-1-benzofuran-3-carbonyl)phenol3562-84-3Xanthine oxidase inhibitor5.52-3.830.5--3.8Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Lenhard S.C.
      • Lev M.
      • Webster L.O.
      • Peterson R.A.
      • Goulbourne C.N.
      • Miller R.T.
      • Jucker B.M.
      Hepatic phospholipidosis is associated with altered hepatobiliary function as assessed by gadoxetate dynamic contrast-enhanced magnetic resonance imaging.
      Toxicol. Pathol. 2016; 44: 51-60
      )
      BenfluorexN-(1-methyl-2-(3-[trifluoromethyl]-phenyl)ethyl)amino ethanol benzoate ester23642-66-2Anorectic and hypolipidemic4.269.14102++19.9Yes(
      • Morelli J.K.
      • Buehrle M.
      • Pognan F.
      • Barone L.R.
      • Fieles W.
      • Ciaccio P.J.
      Validation of an in vitro screen for phospholipidosis using a high-content biology platform.
      Cell Biol. Toxicol. 2006; 22: 15-27
      ,
      • Frachon I.
      • Le Gal G.
      • Hill C.
      • Leroyer C.
      Benfluorex withdrawal in France: still be hiding somewhere in the world?.
      J. Pharmacol. Pharmacother. 2011; 2: 307-308
      ,
      • Kohl C.
      • Ravel D.
      • Girard J.
      • Pegorier J.P.
      Effects of benfluorex on fatty acid and glucose metabolism in isolated rat hepatocytes: from metabolic fluxes to gene expression.
      Diabetes. 2002; 51: 2363-2368
      )
      Bepridil hydrochloride1-isobutoxy-2-pyrrolidino-3-(N-benzylanilino) propane hydrochloride74764-40-2Calcium channel blocker5.339.16112++7.17Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Hanumegowda U.M.
      • Wenke G.
      • Regueiro-Ren A.
      • Yordanova R.
      • Corradi J.P.
      • Adams S.P.
      Phospholipidosis as a function of basicity, lipophilicity, and volume of distribution of compounds.
      Chem. Res. Toxicol. 2010; 23: 749-755
      )
      Betaxolol1-{4-[2-(cyclopropylmethoxy) ethyl] phenoxy}-3-[(propan-2-yl) amino]propan-2-ol63659-18-7Beta blocker2.819.67101++0Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Przybylak K.R.
      • Cronin M.T.
      In silico studies of the relationship between chemical structure and drug induced phospholipidosis.
      Mol. Inform. 2011; 30: 415-429
      )
      Bromhexine2-amino-3,5-dibromo-N-cyclohexyl-N-methylbenzylamine hydrochloride611-75-6Mucolytic4.089.32104++30.78Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Heath M.F.
      • Jacobson W.
      The inhibition of lysosomal phospholipase A from rabbit lung by ambroxol and its consequences for pulmonary surfactant.
      Lung. 1985; 163: 337-344
      ,
      • Fusani L.
      • Brown M.
      • Chen H.
      • Ahlberg E.
      • Noeske T.
      Predicting the risk of phospholipidosis with in silico models and an image-based in vitro screen.
      Mol. Pharm. 2017; 14: 4346-4352
      ,
      • Eckert H.
      • Lux M.
      • Lachmann B.
      The role of alveolar macrophages in surfactant turnover. An experimental study with metabolite VIII of bromhexine (Ambroxol).
      Lung. 1983; 161: 213-218
      )
      Buclizine1-((4-chlorophenyl)phenylmethyl)-4-((4-(1,1-dimethylethyl)phenyl)methyl)piperazine82-95-1Antihistamine6.168.04103++9.13Yes(
      • Kruhlak N.L.
      • Choi S.S.
      • Contrera J.F.
      • Weaver J.L.
      • Willard J.M.
      • Hastings K.L.
      • Sancilio L.F.
      Development of a phospholipidosis database and predictive quantitative structure-activity relationship (QSAR) models.
      Toxicol. Mech. Methods. 2008; 18: 217-227
      ,
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      )
      Bromocriptine(4R,7R)-10-bromo-N-[(1S,2S,4R,7S)-2-hydroxy-7-(2-methylpropyl)-5,8-dioxo-4-(propan-2-yl)-3-oxa-6,9-diazatricyclo[7.3.0.0ˆ{2,6}]dodecan-4-yl]-6-methyl-6,11diazatetracyclo[7.6.1.0ˆ{2,7}.0ˆ{12,16}]hexadeca-1(16),2,9,12,14-pentaene-4-carboxamide25614-03-3Dopamine promoter3.26.7155-+125Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Frohlich E.
      Toxicity of orally inhaled drug formulations at the alveolar barrier: parameters for initial biological screening.
      Drug Deliv. 2017; 24: 891-905
      )
      Chloroquine7-chloro-N-[5-(diethylamino)pentan-2-yl]quinolin-4-amine54-05-7Immunosuppress-sive and anti-parasitic4.6310.32128++655YesH, R, D, M(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Fischer H.
      • Atzpodien E.A.
      • Csato M.
      • Doessegger L.
      • Lenz B.
      • Schmitt G.
      • Singer T.
      In silico assay for assessing phospholipidosis potential of small druglike molecules: training, validation, and refinement using several data sets.
      J. Med. Chem. 2012; 55: 126-139
      ,
      • Hanumegowda U.M.
      • Wenke G.
      • Regueiro-Ren A.
      • Yordanova R.
      • Corradi J.P.
      • Adams S.P.
      Phospholipidosis as a function of basicity, lipophilicity, and volume of distribution of compounds.
      Chem. Res. Toxicol. 2010; 23: 749-755
      ,
      • Shahane S.A.
      • Huang R.
      • Gerhold D.
      • Baxa U.
      • Austin C.P.
      • Xia M.
      Detection of phospholipidosis induction: a cell-based assay in high-throughput and high-content format.
      J. Biomol. Screen. 2014; 19: 66-76
      ,
      • Tochitani T.
      • Yamashita A.
      • Kouchi M.
      • Fujii Y.
      • Matsumoto I.
      • Miyawaki I.
      • Yamada T.
      • Funabashi H.
      Changes in plasma concentrations of corticosterone and its precursors after ketoconazole administration in rats: An application of simultaneous measurement of multiple steroids using LC-MS/MS.
      Exp. Toxicol. Pathol. 2016; 68: 125-131
      ,
      • Przybylak K.R.
      • Cronin M.T.
      In silico studies of the relationship between chemical structure and drug induced phospholipidosis.
      Mol. Inform. 2011; 30: 415-429
      ,
      • Pappu A.S.
      • Yazaki P.J.
      • Hostetler K.Y.
      Inhibition of purified lysosomal phospholipase A1 by beta-adrenoceptor blockers.
      Biochem. Pharmacol. 1985; 34: 521-524
      ,
      • Gregory M.H.
      • Rutty D.A.
      • Wood R.D.
      Differences in the retinotoxic action of chloroquine and phenothiazine derivatives.
      J. Pathol. 1970; 102: 139-150
      ,
      • Rosenthal A.R.
      • Kolb H.
      • Bergsma D.
      • Huxsoll D.
      • Hopkins J.L.
      Chloroquine retinopathy in the rhesus monkey.
      Invest. Ophthalmol. Vis. Sci. 1978; 17: 1158-1175
      ,
      • Meanwell N.A.
      Fluorine and fluorinated motifs in the design and application of bioisosteres for drug design.
      J. Med. Chem. 2018; 61: 5822-5880
      )
      Chlorpheniramine[3-(4-chlorophenyl)-3-(pyridin-2-yl) propyl] dimethylamine132-22-9Antihistamine3.389.47101++147Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Morelli J.K.
      • Buehrle M.
      • Pognan F.
      • Barone L.R.
      • Fieles W.
      • Ciaccio P.J.
      Validation of an in vitro screen for phospholipidosis using a high-content biology platform.
      Cell Biol. Toxicol. 2006; 22: 15-27
      ,
      • Low Y.
      • Uehara T.
      • Minowa Y.
      • Yamada H.
      • Ohno Y.
      • Urushidani T.
      • Sedykh A.
      • Muratov E.
      • Kuz'min V.
      • Fourches D.
      • Zhu H.
      • Rusyn I.
      • Tropsha A.
      Predicting drug-induced hepatotoxicity using QSAR and toxicogenomics approaches.
      Chem. Res. Toxicol. 2011; 24: 1251-1262
      )
      Chlorprothixene3-[(9Z)-2-chloro-9H-thioxanthen-9-ylidene]propyl}dimethylamine11-59-7Antipsychotic5.189.76122++7.78Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      )
      Chlorpromazine[3-(2-chloro-10H-phenothiazin-10-yl)propyl] dimethylamine50-53-3Antipsychotic5.419.3116++9.01YesR, D(
      • Sawada H.
      • Takami K.
      • Asahi S.
      A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system.
      Toxicol. Sci. 2005; 83: 282-292
      ,
      • Nioi P.
      • Perry B.K.
      • Wang E.J.
      • Gu Y.Z.
      • Snyder R.D.
      In vitro detection of drug-induced phospholipidosis using gene expression and fluorescent phospholipid based methodologies.
      Toxicol. Sci. 2007; 99: 162-173
      ,
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Fischer H.
      • Atzpodien E.A.
      • Csato M.
      • Doessegger L.
      • Lenz B.
      • Schmitt G.
      • Singer T.
      In silico assay for assessing phospholipidosis potential of small druglike molecules: training, validation, and refinement using several data sets.
      J. Med. Chem. 2012; 55: 126-139
      ,
      • Hanumegowda U.M.
      • Wenke G.
      • Regueiro-Ren A.
      • Yordanova R.
      • Corradi J.P.
      • Adams S.P.
      Phospholipidosis as a function of basicity, lipophilicity, and volume of distribution of compounds.
      Chem. Res. Toxicol. 2010; 23: 749-755
      ,
      • Shahane S.A.
      • Huang R.
      • Gerhold D.
      • Baxa U.
      • Austin C.P.
      • Xia M.
      Detection of phospholipidosis induction: a cell-based assay in high-throughput and high-content format.
      J. Biomol. Screen. 2014; 19: 66-76
      ,
      • Atienzar F.
      • Gerets H.
      • Dufrane S.
      • Tilmant K.
      • Cornet M.
      • Dhalluin S.
      • Ruty B.
      • Rose G.
      • Canning M.
      Determination of phospholipidosis potential based on gene expression analysis in HepG2 cells.
      Toxicol. Sci. 2007; 96: 101-114
      ,
      • Przybylak K.R.
      • Cronin M.T.
      In silico studies of the relationship between chemical structure and drug induced phospholipidosis.
      Mol. Inform. 2011; 30: 415-429
      )
      Cinnarizine1-(diphenyl methyl)-4-(3-phenylprop-2-en-1-yl) piperazine298-57-7Antihistamine5.778.44105++40.6Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Kornhuber J.
      • Henkel A.W.
      • Groemer T.W.
      • Stadtler S.
      • Welzel O.
      • Tripal P.
      • Rotter A.
      • Bleich S.
      • Trapp S.
      Lipophilic cationic drugs increase the permeability of lysosomal membranes in a cell culture system.
      J. Cell Physiol. 2010; 224: 152-164
      )
      Citalopram1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile59729-33-8Antidepressant3.769.78110++19.5YesYes(
      • Kruhlak N.L.
      • Choi S.S.
      • Contrera J.F.
      • Weaver J.L.
      • Willard J.M.
      • Hastings K.L.
      • Sancilio L.F.
      Development of a phospholipidosis database and predictive quantitative structure-activity relationship (QSAR) models.
      Toxicol. Mech. Methods. 2008; 18: 217-227
      ,
      • Nioi P.
      • Perry B.K.
      • Wang E.J.
      • Gu Y.Z.
      • Snyder R.D.
      In vitro detection of drug-induced phospholipidosis using gene expression and fluorescent phospholipid based methodologies.
      Toxicol. Sci. 2007; 99: 162-173
      ,
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Fischer H.
      • Atzpodien E.A.
      • Csato M.
      • Doessegger L.
      • Lenz B.
      • Schmitt G.
      • Singer T.
      In silico assay for assessing phospholipidosis potential of small druglike molecules: training, validation, and refinement using several data sets.
      J. Med. Chem. 2012; 55: 126-139
      ,
      • Morelli J.K.
      • Buehrle M.
      • Pognan F.
      • Barone L.R.
      • Fieles W.
      • Ciaccio P.J.
      Validation of an in vitro screen for phospholipidosis using a high-content biology platform.
      Cell Biol. Toxicol. 2006; 22: 15-27
      ,
      • Hanumegowda U.M.
      • Wenke G.
      • Regueiro-Ren A.
      • Yordanova R.
      • Corradi J.P.
      • Adams S.P.
      Phospholipidosis as a function of basicity, lipophilicity, and volume of distribution of compounds.
      Chem. Res. Toxicol. 2010; 23: 749-755
      ,
      • Shahane S.A.
      • Huang R.
      • Gerhold D.
      • Baxa U.
      • Austin C.P.
      • Xia M.
      Detection of phospholipidosis induction: a cell-based assay in high-throughput and high-content format.
      J. Biomol. Screen. 2014; 19: 66-76
      ,
      • Przybylak K.R.
      • Cronin M.T.
      In silico studies of the relationship between chemical structure and drug induced phospholipidosis.
      Mol. Inform. 2011; 30: 415-429
      )
      Clemastine(2R)-2-{2-[(1R)-1-(4-chlorophenyl)-1-phenylethoxy] ethyl-1-methylpyrrolidine14976-57-9Antihistamine5.299.55119++13.21Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      )
      Clenbuterol4-amino-3,5-dichloro-α-[[(1,1-dimethylethyl)amino]methyl]-benzenemethanol, monohydrochloride21898-19-1Muscle relaxer decongestant, bronchodilator2.949.63101++7298Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      )
      Clindamycin(2S,4R)-N-{2-chloro-1-[(2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(methylsulfanyl)oxan-2-yl]propyl}-1-methyl-4-propylpyrrolidine-2-carboxamide18323-44-9Antibiotic2.167.5561.7-+NDYesYes(
      • Kruhlak N.L.
      • Choi S.S.
      • Contrera J.F.
      • Weaver J.L.
      • Willard J.M.
      • Hastings K.L.
      • Sancilio L.F.
      Development of a phospholipidosis database and predictive quantitative structure-activity relationship (QSAR) models.
      Toxicol. Mech. Methods. 2008; 18: 217-227
      ,
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Hanumegowda U.M.
      • Wenke G.
      • Regueiro-Ren A.
      • Yordanova R.
      • Corradi J.P.
      • Adams S.P.
      Phospholipidosis as a function of basicity, lipophilicity, and volume of distribution of compounds.
      Chem. Res. Toxicol. 2010; 23: 749-755
      ,
      • Przybylak K.R.
      • Cronin M.T.
      In silico studies of the relationship between chemical structure and drug induced phospholipidosis.
      Mol. Inform. 2011; 30: 415-429
      )
      ClofazimineN,5-bis(4-chlorophenyl)-3,5-dihydro-3-(isopropylimino)phenazin-2-amine2030-63-9Anti-mycobacterial, anti-inflammatory properties7.669.29145++10.8Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Baik J.
      • Rosania G.R.
      Macrophages sequester clofazimine in an intracellular liquid crystal-like supramolecular organization.
      PLoS One. 2012; 7e47494
      ,
      • Baik J.
      • Stringer K.A.
      • Mane G.
      • Rosania G.R.
      Multiscale distribution and bioaccumulation analysis of clofazimine reveals a massive immune system-mediated xenobiotic sequestration response.
      Antimicrob. Agents Chemother. 2013; 57: 1218-1230
      )
      Clomipramine(3-{14-chloro-2-azatricyclo[9.4.0.03,8]pentadeca-1(11), 3,5,7,12,14-hexaen-2-yl}propyl)dimethylamine303-49-1Antidepressant5.049.2104++17YesYes(
      • Sawada H.
      • Takami K.
      • Asahi S.
      A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system.
      Toxicol. Sci. 2005; 83: 282-292
      ,
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Fischer H.
      • Atzpodien E.A.
      • Csato M.
      • Doessegger L.
      • Lenz B.
      • Schmitt G.
      • Singer T.
      In silico assay for assessing phospholipidosis potential of small druglike molecules: training, validation, and refinement using several data sets.
      J. Med. Chem. 2012; 55: 126-139
      ,
      • Morelli J.K.
      • Buehrle M.
      • Pognan F.
      • Barone L.R.
      • Fieles W.
      • Ciaccio P.J.
      Validation of an in vitro screen for phospholipidosis using a high-content biology platform.
      Cell Biol. Toxicol. 2006; 22: 15-27
      ,
      • Hanumegowda U.M.
      • Wenke G.
      • Regueiro-Ren A.
      • Yordanova R.
      • Corradi J.P.
      • Adams S.P.
      Phospholipidosis as a function of basicity, lipophilicity, and volume of distribution of compounds.
      Chem. Res. Toxicol. 2010; 23: 749-755
      ,
      • Shahane S.A.
      • Huang R.
      • Gerhold D.
      • Baxa U.
      • Austin C.P.
      • Xia M.
      Detection of phospholipidosis induction: a cell-based assay in high-throughput and high-content format.
      J. Biomol. Screen. 2014; 19: 66-76
      ,
      • Atienzar F.
      • Gerets H.
      • Dufrane S.
      • Tilmant K.
      • Cornet M.
      • Dhalluin S.
      • Ruty B.
      • Rose G.
      • Canning M.
      Determination of phospholipidosis potential based on gene expression analysis in HepG2 cells.
      Toxicol. Sci. 2007; 96: 101-114
      )
      Cloperastin1-{2-[(4-chlorophenyl) (phenyl)methoxy] ethyl} piperidine3703-76-2Antihistamine5.118.82104++40.9Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Kornhuber J.
      • Muehlbacher M.
      • Trapp S.
      • Pechmann S.
      • Friedl A.
      • Reichel M.
      • Mühle C.
      • Terfloth L.
      • Groemer T.W.
      • Spitzer G.M.
      • Liedl K.R.
      • Gulbins E.
      • Tripal P.
      Identification of novel functional inhibitors of acid sphingomyelinase.
      PLoS One. 2011; 6e23852
      )
      Clozapine8-Chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]-diazepine34233-69-7Antipsychotic3.237.3564.5-+10.8YesYes(
      • Sawada H.
      • Takami K.
      • Asahi S.
      A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system.
      Toxicol. Sci. 2005; 83: 282-292
      ,
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Fischer H.
      • Atzpodien E.A.
      • Csato M.
      • Doessegger L.
      • Lenz B.
      • Schmitt G.
      • Singer T.
      In silico assay for assessing phospholipidosis potential of small druglike molecules: training, validation, and refinement using several data sets.
      J. Med. Chem. 2012; 55: 126-139
      ,
      • Atienzar F.
      • Gerets H.
      • Dufrane S.
      • Tilmant K.
      • Cornet M.
      • Dhalluin S.
      • Ruty B.
      • Rose G.
      • Canning M.
      Determination of phospholipidosis potential based on gene expression analysis in HepG2 cells.
      Toxicol. Sci. 2007; 96: 101-114
      ,
      • Przybylak K.R.
      • Cronin M.T.
      In silico studies of the relationship between chemical structure and drug induced phospholipidosis.
      Mol. Inform. 2011; 30: 415-429
      )
      Corticosterone(1S,2R,10S,11S,14S,15S,17S)-17-hydroxy-14-(2-hydroxyacetyl)-2,15-dimethyltetracyclo[8.7.0.02,7.011,15]heptadec-6-en-5-one50-22-6Glucocorticoid2.09-0.264.4--163Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Tochitani T.
      • Yamashita A.
      • Kouchi M.
      • Fujii Y.
      • Matsumoto I.
      • Miyawaki I.
      • Yamada T.
      • Funabashi H.
      Changes in plasma concentrations of corticosterone and its precursors after ketoconazole administration in rats: An application of simultaneous measurement of multiple steroids using LC-MS/MS.
      Exp. Toxicol. Pathol. 2016; 68: 125-131
      )
      Cyclazosin1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furanylcarbonyl) decahydroquinoxaline146929-33-1Adrenoceptor antagonist3.49.89109++30.75Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Shahane S.A.
      • Huang R.
      • Gerhold D.
      • Baxa U.
      • Austin C.P.
      • Xia M.
      Detection of phospholipidosis induction: a cell-based assay in high-throughput and high-content format.
      J. Biomol. Screen. 2014; 19: 66-76
      )
      Cyclobenzaprinedimethyl(3-{tricyclo[9.4.0.03,8]pentadeca-1(15),3,5, 7,9,11,13-heptaen-2-ylidene}propyl)amine303-53-7Muscle relaxant4.738.4794++6.24YesYes(
      • Shahane S.A.
      • Huang R.
      • Gerhold D.
      • Baxa U.
      • Austin C.P.
      • Xia M.
      Detection of phospholipidosis induction: a cell-based assay in high-throughput and high-content format.
      J. Biomol. Screen. 2014; 19: 66-76
      )
      Cyclopentolate2-(dimethylamino)ethyl 2-(1-hydroxycyclopentyl)-2-phenylacetate515-15-2Anticholinergic2.328.4276-+32.2Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Xu L.
      • Sheflin L.G.
      • Porter N.A.
      • Fliesler S.J.
      7-Dehydrocholesterol-derived oxysterols and retinal degeneration in a rat model of Smith-Lemli-Opitz syndrome.
      Biochim. Biophys. Acta. 2012; 1821: 877-883
      ,
      • Talamo J.H.
      • D'Amico D.J.
      • Hanninen L.A.
      • Kenyon K.R.
      • Shanks E.T.
      The influence of aphakia and vitrectomy on experimental retinal toxicity of aminoglycoside antibiotics.
      Am. J. Ophthalmol. 1985; 100: 840-847
      )
      Desipramine(3-{2-azatricyclo [9.4.0.0] pentadeca-1(15),3,5,7,11,13-hexaen-2-yl}propyl)(methyl)amine58-28-6Antidepressant4.0210.02117++25.69YesR(
      • Morelli J.K.
      • Buehrle M.
      • Pognan F.
      • Barone L.R.
      • Fieles W.
      • Ciaccio P.J.
      Validation of an in vitro screen for phospholipidosis using a high-content biology platform.
      Cell Biol. Toxicol. 2006; 22: 15-27
      ,
      • Hanumegowda U.M.
      • Wenke G.
      • Regueiro-Ren A.
      • Yordanova R.
      • Corradi J.P.
      • Adams S.P.
      Phospholipidosis as a function of basicity, lipophilicity, and volume of distribution of compounds.
      Chem. Res. Toxicol. 2010; 23: 749-755
      ,
      • Shahane S.A.
      • Huang R.
      • Gerhold D.
      • Baxa U.
      • Austin C.P.
      • Xia M.
      Detection of phospholipidosis induction: a cell-based assay in high-throughput and high-content format.
      J. Biomol. Screen. 2014; 19: 66-76
      ,
      • Przybylak K.R.
      • Cronin M.T.
      In silico studies of the relationship between chemical structure and drug induced phospholipidosis.
      Mol. Inform. 2011; 30: 415-429
      ,
      • Scuntaro I.
      • Kientsch U.
      • Wiesmann U.N.
      • Honegger U.E.
      Inhibition by vitamin E of drug accumulation and of phospholipidosis induced by desipramine and other cationic amphiphilic drugs in human cultured cells.
      Br. J. Pharmacol. 1996; 119: 829-834
      )
      Dibenzosuberane10,11-dihydro-5H-dibenzo [a, d] cycloheptene-833-48-7833-48-7Protein inhibitor4.710122++346Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      )
      Diphenhydramine2-[(4-methyl-α-phenyl benzyl) oxy]ethyl (dimethyl) ammonium chloride147-24-0Antihistamine3.278.8789.4-+270Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      )
      Doxepindimethyl(3-{9-oxatricyclo[9.4.0.0ˆ[1]]pentadeca-1(15),3,5,7,11,13-hexaen-2-ylidene}propyl)amine1668-19-5Psychotropic4.299.76114++301YesYes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Shahane S.A.
      • Huang R.
      • Gerhold D.
      • Baxa U.
      • Austin C.P.
      • Xia M.
      Detection of phospholipidosis induction: a cell-based assay in high-throughput and high-content format.
      J. Biomol. Screen. 2014; 19: 66-76
      )
      Drofeninehexahydroadiphenine548-66-3Anticholinergic5.39.21113++7.29Yes(
      • Morelli J.K.
      • Buehrle M.
      • Pognan F.
      • Barone L.R.
      • Fieles W.
      • Ciaccio P.J.
      Validation of an in vitro screen for phospholipidosis using a high-content biology platform.
      Cell Biol. Toxicol. 2006; 22: 15-27
      ,
      • Kornhuber J.
      • Tripal P.
      • Gulbins E.
      • Muehlbacher M.
      Functional inhibitors of acid sphingomyelinase (FIASMAs).
      Handb. Exp. Pharmacol. 2013; : 169-186
      )
      Dutasteride(1S,2R,7R,10S,11S,14S,15S)-N-[2,5-bis (trifluoromethyl) phenyl]-2,15-dimethyl-5-oxo-6-azatetracyclo[8.7.0.02,7.011,15]heptadec-3-ene-14-carboxamide164656-23-95α-reductase inhibitor6.82.1750.9++1048Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      )
      Encainide4-methoxy-N-{2-[2-(1-methylpiperidin-2-yl)ethyl] phenyl} benzamide66778-36-7Sodium channel blocker49.41105++76.09Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • MacNeil D.J.
      The side effect profile of class III antiarrhythmic drugs: focus on d,l-sotalol.
      Am. J. Cardiol. 1997; 80: 90G-98G
      )
      Erythromycin(3R,4S,5S,6R,7R,9R,11R,12R,13S,14R)-6-{[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy}-14-ethyl-7,12,13-trihydroxy-4-{[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-1-oxacyclotetradecane-2,10-dione114-07-8Bacteriostatic antibiotic2.378.3875.9+117YesR, D(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Fischer H.
      • Atzpodien E.A.
      • Csato M.
      • Doessegger L.
      • Lenz B.
      • Schmitt G.
      • Singer T.
      In silico assay for assessing phospholipidosis potential of small druglike molecules: training, validation, and refinement using several data sets.
      J. Med. Chem. 2012; 55: 126-139
      ,
      • Hanumegowda U.M.
      • Wenke G.
      • Regueiro-Ren A.
      • Yordanova R.
      • Corradi J.P.
      • Adams S.P.
      Phospholipidosis as a function of basicity, lipophilicity, and volume of distribution of compounds.
      Chem. Res. Toxicol. 2010; 23: 749-755
      ,
      • Atienzar F.
      • Gerets H.
      • Dufrane S.
      • Tilmant K.
      • Cornet M.
      • Dhalluin S.
      • Ruty B.
      • Rose G.
      • Canning M.
      Determination of phospholipidosis potential based on gene expression analysis in HepG2 cells.
      Toxicol. Sci. 2007; 96: 101-114
      ,
      • Gray J.E.
      • Purmalis A.
      • Purmalis B.
      • Mathews J.
      Ultrastructural studies of the hepatic changes brought about by Clindamycin and Erythromycin in animals.
      Toxicol. Appl. Pharmacol. 1971; 19: 217-233
      )
      Etomidateethyl 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylate33125-97-2Anesthetic34.5429.6--1155Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Przybylak K.R.
      • Cronin M.T.
      In silico studies of the relationship between chemical structure and drug induced phospholipidosis.
      Mol. Inform. 2011; 30: 415-429
      )
      Fenofibrate2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropanoic acid isopropyl ester49562-28-9Cholesterol lowering5.3-4.928.1-31.582.25Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Qi C.
      • Zhu Y.
      • Reddy J.K.
      Peroxisome proliferator-activated receptors, coactivators, and downstream targets.
      Cell Biochem. Biophys. 2000; 32: 187-204
      )
      Fexofenadine2-(4-{1-hydroxy-4-[4-(hydroxydiphenylmethyl) piperidin-1-yl]butyl} phenyl)-2-methylpropanoic acid83799-24-0Antihistamine5.029.01106++179Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Perez Martin J.M.
      • Labrador V.
      • Fernandez Freire P.
      • Molero M.L.
      • Hazen M.J.
      Ultrastructural changes induced in HeLa cells after phototoxic treatment with harmine.
      J. Appl. Toxicol. 2004; 24: 197-201
      )
      Fipexide1-(2-[4-chlorophenoxy]acetyl)-4-(3,4-methylenedioxybenzyl)piperazine34161-24-5Attention deficit2.956.0945.7--17.19Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      )
      Flunarizine1-[bis(4-fluorophenyl)methyl]-4-[(2E)-3-phenylprop-2-en-1-yl]piperazine52468-60-7Calcium entry blocker5.37.685.9-+7.49Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Chan K.
      • Truong D.
      • Shangari N.
      • O'Brien P.J.
      Drug-induced mitochondrial toxicity.
      Expert Opin. Drug Metab. Toxicol. 2005; 1: 655-669
      )
      Fluoxetinemethyl({3-phenyl-3-[4-(trifluoromethyl) phenoxy] propyl}) amine54910-89-3Antidepressant4.59.8112++13.5YesH,R,M(
      • Sawada H.
      • Takami K.
      • Asahi S.
      A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system.
      Toxicol. Sci. 2005; 83: 282-292
      ,
      • Nioi P.
      • Perry B.K.
      • Wang E.J.
      • Gu Y.Z.
      • Snyder R.D.
      In vitro detection of drug-induced phospholipidosis using gene expression and fluorescent phospholipid based methodologies.
      Toxicol. Sci. 2007; 99: 162-173
      ,
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Fischer H.
      • Atzpodien E.A.
      • Csato M.
      • Doessegger L.
      • Lenz B.
      • Schmitt G.
      • Singer T.
      In silico assay for assessing phospholipidosis potential of small druglike molecules: training, validation, and refinement using several data sets.
      J. Med. Chem. 2012; 55: 126-139
      ,
      • Morelli J.K.
      • Buehrle M.
      • Pognan F.
      • Barone L.R.
      • Fieles W.
      • Ciaccio P.J.
      Validation of an in vitro screen for phospholipidosis using a high-content biology platform.
      Cell Biol. Toxicol. 2006; 22: 15-27
      ,
      • Hanumegowda U.M.
      • Wenke G.
      • Regueiro-Ren A.
      • Yordanova R.
      • Corradi J.P.
      • Adams S.P.
      Phospholipidosis as a function of basicity, lipophilicity, and volume of distribution of compounds.
      Chem. Res. Toxicol. 2010; 23: 749-755
      ,
      • Shahane S.A.
      • Huang R.
      • Gerhold D.
      • Baxa U.
      • Austin C.P.
      • Xia M.
      Detection of phospholipidosis induction: a cell-based assay in high-throughput and high-content format.
      J. Biomol. Screen. 2014; 19: 66-76
      ,
      • Atienzar F.
      • Gerets H.
      • Dufrane S.
      • Tilmant K.
      • Cornet M.
      • Dhalluin S.
      • Ruty B.
      • Rose G.
      • Canning M.
      Determination of phospholipidosis potential based on gene expression analysis in HepG2 cells.
      Toxicol. Sci. 2007; 96: 101-114
      ,
      • Przybylak K.R.
      • Cronin M.T.
      In silico studies of the relationship between chemical structure and drug induced phospholipidosis.
      Mol. Inform. 2011; 30: 415-429
      ,
      • Kazmi F.
      • Hensley T.
      • Pope C.
      • Funk R.S.
      • Loewen G.J.
      • Buckley D.B.
      • Parkinson A.
      Lysosomal sequestration (trapping) of lipophilic amine (cationic amphiphilic) drugs in immortalized human hepatocytes (Fa2N-4 cells).
      Drug Metab. Dispos. 2013; 41: 897-905
      ,
      • Bendele R.A.
      • Adams E.R.
      • Hoffman W.P.
      • Gries C.L.
      • Morton D.M.
      Carcinogenicity studies of fluoxetine hydrochloride in rats and mice.
      Cancer Res. 1992; 52: 6931-6935
      )
      Flufenamic acid2-{[3-(trifluoromethyl)phenyl]amino}benzoic acid530-78-9Analgesic, anti-inflammatory, antipyretic5.25-2.132--177.9Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • McMillian M.K.
      • Grant E.R.
      • Zhong Z.
      • Parker J.B.
      • Li L.
      • Zivin R.A.
      • Burczynski M.E.
      • Johnson M.D.
      Nile Red binding to HepG2 cells: an improved assay for in vitro studies of hepatosteatosis.
      In Vitr. Mol. Toxicol. 2001; 14: 177-190
      )
      Gentisic acid2,5-dihydroxybenzoic acid sodium salt4955-90-2Anti-inflammatory, antioxidant-1.1-5.934.8--99.4Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Ginoulhiac E.
      • Semenza F.
      • Mainardi L.
      [Toxicity and pharmacologic effects of gentisic acid].
      Boll Soc. Ital. Biol. Sper. 1950; 26: 583-585
      )
      Hydroxyzine2-(2-{4-[(4-chlorophenyl) (phenyl) methyl] piperazin-1-yl} ethoxy)ethan-1-ol68-88-2Antihistaminic3.437.8272.9-+63R(
      • Fischer H.
      • Atzpodien E.A.
      • Csato M.
      • Doessegger L.
      • Lenz B.
      • Schmitt G.
      • Singer T.
      In silico assay for assessing phospholipidosis potential of small druglike molecules: training, validation, and refinement using several data sets.
      J. Med. Chem. 2012; 55: 126-139
      ,
      • Hanumegowda U.M.
      • Wenke G.
      • Regueiro-Ren A.
      • Yordanova R.
      • Corradi J.P.
      • Adams S.P.
      Phospholipidosis as a function of basicity, lipophilicity, and volume of distribution of compounds.
      Chem. Res. Toxicol. 2010; 23: 749-755
      ,
      • Meanwell N.A.
      Fluorine and fluorinated motifs in the design and application of bioisosteres for drug design.
      J. Med. Chem. 2018; 61: 5822-5880
      ,
      • Hruban Z.
      • Slesers A.
      • Hopkins E.
      Drug-induced and naturally occurring myeloid bodies.
      Lab. Invest. 1972; 27: 62-70
      )
      Imipramine(3-{2-azatricyclo[9.4.0.03,8]pentadeca-1(15),3, 5,7,11, 13-hexaen-2-yl}propyl)dimethylamine50-49-7Antidepressant4.89.2108++27.6YesR(
      • Sawada H.
      • Takami K.
      • Asahi S.
      A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system.
      Toxicol. Sci. 2005; 83: 282-292
      ,
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Fischer H.
      • Atzpodien E.A.
      • Csato M.
      • Doessegger L.
      • Lenz B.
      • Schmitt G.
      • Singer T.
      In silico assay for assessing phospholipidosis potential of small druglike molecules: training, validation, and refinement using several data sets.
      J. Med. Chem. 2012; 55: 126-139
      ,
      • Morelli J.K.
      • Buehrle M.
      • Pognan F.
      • Barone L.R.
      • Fieles W.
      • Ciaccio P.J.
      Validation of an in vitro screen for phospholipidosis using a high-content biology platform.
      Cell Biol. Toxicol. 2006; 22: 15-27
      ,
      • Hanumegowda U.M.
      • Wenke G.
      • Regueiro-Ren A.
      • Yordanova R.
      • Corradi J.P.
      • Adams S.P.
      Phospholipidosis as a function of basicity, lipophilicity, and volume of distribution of compounds.
      Chem. Res. Toxicol. 2010; 23: 749-755
      ,
      • Shahane S.A.
      • Huang R.
      • Gerhold D.
      • Baxa U.
      • Austin C.P.
      • Xia M.
      Detection of phospholipidosis induction: a cell-based assay in high-throughput and high-content format.
      J. Biomol. Screen. 2014; 19: 66-76
      ,
      • Przybylak K.R.
      • Cronin M.T.
      In silico studies of the relationship between chemical structure and drug induced phospholipidosis.
      Mol. Inform. 2011; 30: 415-429
      ,
      • Drenckhahn D.
      • Lullmann-Rauch R.
      Experimental myopathy induced by amphiphilic cationic compounds including several psychotropic drugs.
      Neuroscience. 1979; 4: 549-562
      ,
      • Glassman A.H.
      • Perel J.M.
      The clinical pharmacology of imipramine. Implications for therapeutics.
      Arch. Gen. Psychiatry. 1973; 28: 649-653
      )
      IndoraminN-{1-[2-(1H-indol-3-yl)ethyl]piperidin-4-yl} benzamide26844-12-2Antiadrenergic4.029.59108++123.9YesR(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Hanumegowda U.M.
      • Wenke G.
      • Regueiro-Ren A.
      • Yordanova R.
      • Corradi J.P.
      • Adams S.P.
      Phospholipidosis as a function of basicity, lipophilicity, and volume of distribution of compounds.
      Chem. Res. Toxicol. 2010; 23: 749-755
      ,
      • Przybylak K.R.
      • Cronin M.T.
      In silico studies of the relationship between chemical structure and drug induced phospholipidosis.
      Mol. Inform. 2011; 30: 415-429
      )
      Ketoconazole1-[4-(4-{[2-(2,4-dichlorophenyl)-2-(1H-imidazole-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)piperazin-1-yl]ethan-1-one65277-42-1Antifungal4.356.7564.5-+39YesM(
      • Sawada H.
      • Takami K.
      • Asahi S.
      A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system.
      Toxicol. Sci. 2005; 83: 282-292
      ,
      • Nioi P.
      • Perry B.K.
      • Wang E.J.
      • Gu Y.Z.
      • Snyder R.D.
      In vitro detection of drug-induced phospholipidosis using gene expression and fluorescent phospholipid based methodologies.
      Toxicol. Sci. 2007; 99: 162-173
      ,
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Fischer H.
      • Atzpodien E.A.
      • Csato M.
      • Doessegger L.
      • Lenz B.
      • Schmitt G.
      • Singer T.
      In silico assay for assessing phospholipidosis potential of small druglike molecules: training, validation, and refinement using several data sets.
      J. Med. Chem. 2012; 55: 126-139
      ,
      • Hanumegowda U.M.
      • Wenke G.
      • Regueiro-Ren A.
      • Yordanova R.
      • Corradi J.P.
      • Adams S.P.
      Phospholipidosis as a function of basicity, lipophilicity, and volume of distribution of compounds.
      Chem. Res. Toxicol. 2010; 23: 749-755
      ,
      • Shahane S.A.
      • Huang R.
      • Gerhold D.
      • Baxa U.
      • Austin C.P.
      • Xia M.
      Detection of phospholipidosis induction: a cell-based assay in high-throughput and high-content format.
      J. Biomol. Screen. 2014; 19: 66-76
      ,
      • Przybylak K.R.
      • Cronin M.T.
      In silico studies of the relationship between chemical structure and drug induced phospholipidosis.
      Mol. Inform. 2011; 30: 415-429
      )
      Ketotifen4-(1-methylpiperidin-4-ylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-9,10-dione34580-14-8Antihistamine2.27.1556-+19.68Yes(
      • Sawada H.
      • Takami K.
      • Asahi S.
      A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system.
      Toxicol. Sci. 2005; 83: 282-292
      ,
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Hanumegowda U.M.
      • Wenke G.
      • Regueiro-Ren A.
      • Yordanova R.
      • Corradi J.P.
      • Adams S.P.
      Phospholipidosis as a function of basicity, lipophilicity, and volume of distribution of compounds.
      Chem. Res. Toxicol. 2010; 23: 749-755
      ,
      • Reasor M.J.
      A review of the biology and toxicologic implications of the induction of lysosomal lamellar bodies by drugs.
      Toxicol. Appl. Pharmacol. 1989; 97: 47-56
      )
      Lercanidipine3-{1-[(3,3-diphenylpropyl)(methyl)amino]-2-methylpropan-2-yl} 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate100427-26-7Calcium channel blocker6.49.36129++37.25Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Salabei J.K.
      • Balakumaran A.
      • Frey J.C.
      • Boor P.J.
      • Treinen-Moslen M.
      • Conklin D.J.
      Verapamil stereoisomers induce antiproliferative effects in vascular smooth muscle cells via autophagy.
      Toxicol. Appl. Pharmacol. 2012; 262: 265-272
      )
      Lofepramine2-[(3-{2-azatricyclo[9.4.0.0ˆ{3,8}]pentadeca-1(15),3,5,7,11,13-hexaen-2-yl}propyl) (methyl) amino]-1-(4-chlorophenyl) ethan-1-one23047-25-8Antidepressant6.116.5380-+13.25Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      )
      Loperamide4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-N,N-dimethyl-2,2-diphenylbutanamide53179-11-6Antidiarrheal4.449.41108++149.12Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      )
      Loratadineethyl 4-{13-chloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaen-2-ylidene}piperidine-1-carboxylate79794-75-5Antihistamine4.84.3341.8--8.94Yes(
      • Sawada H.
      • Takami K.
      • Asahi S.
      A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system.
      Toxicol. Sci. 2005; 83: 282-292
      ,
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Hanumegowda U.M.
      • Wenke G.
      • Regueiro-Ren A.
      • Yordanova R.
      • Corradi J.P.
      • Adams S.P.
      Phospholipidosis as a function of basicity, lipophilicity, and volume of distribution of compounds.
      Chem. Res. Toxicol. 2010; 23: 749-755
      ,
      • Shahane S.A.
      • Huang R.
      • Gerhold D.
      • Baxa U.
      • Austin C.P.
      • Xia M.
      Detection of phospholipidosis induction: a cell-based assay in high-throughput and high-content format.
      J. Biomol. Screen. 2014; 19: 66-76
      ,
      • Przybylak K.R.
      • Cronin M.T.
      In silico studies of the relationship between chemical structure and drug induced phospholipidosis.
      Mol. Inform. 2011; 30: 415-429
      ,
      • Takagi M.
      • Sanoh S.
      • Santoh M.
      • Ejiri Y.
      • Kotake Y.
      • Ohta S.
      Detection of metabolic activation leading to drug-induced phospholipidosis in rat hepatocyte spheroids.
      J. Toxicol. Sci. 2016; 41: 155-164
      )
      Mannitol(2R,3R,4R,5R)-hexane-1,2,3,4,5,6-hexol69-65-8Osmotic diuretic-2.712.3159++160Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Tochitani T.
      • Yamashita A.
      • Kouchi M.
      • Fujii Y.
      • Matsumoto I.
      • Miyawaki I.
      • Yamada T.
      • Funabashi H.
      Changes in plasma concentrations of corticosterone and its precursors after ketoconazole administration in rats: An application of simultaneous measurement of multiple steroids using LC-MS/MS.
      Exp. Toxicol. Pathol. 2016; 68: 125-131
      ,
      • Zheng N.
      • Zhang X.
      • Rosania G.R.
      Effect of phospholipidosis on the cellular pharmacokinetics of chloroquine.
      J. Pharmacol. Exp. Ther. 2011; 336: 661-671
      )
      Maprotilinemethyl(3-{tetracyclo [6.6.2.02,7.09,14]hexadeca-2,4,6,9,11, 13-hexaen-1-yl}propyl)amine10262-69-8Antidepressant4.8210.54134++12R(
      • Fischer H.
      • Atzpodien E.A.
      • Csato M.
      • Doessegger L.
      • Lenz B.
      • Schmitt G.
      • Singer T.
      In silico assay for assessing phospholipidosis potential of small druglike molecules: training, validation, and refinement using several data sets.
      J. Med. Chem. 2012; 55: 126-139
      ,
      • Morelli J.K.
      • Buehrle M.
      • Pognan F.
      • Barone L.R.
      • Fieles W.
      • Ciaccio P.J.
      Validation of an in vitro screen for phospholipidosis using a high-content biology platform.
      Cell Biol. Toxicol. 2006; 22: 15-27
      ,
      • Hanumegowda U.M.
      • Wenke G.
      • Regueiro-Ren A.
      • Yordanova R.
      • Corradi J.P.
      • Adams S.P.
      Phospholipidosis as a function of basicity, lipophilicity, and volume of distribution of compounds.
      Chem. Res. Toxicol. 2010; 23: 749-755
      ,
      • Zheng N.
      • Zhang X.
      • Rosania G.R.
      Effect of phospholipidosis on the cellular pharmacokinetics of chloroquine.
      J. Pharmacol. Exp. Ther. 2011; 336: 661-671
      ,
      • Staubli W.
      • Schweizer W.
      • Suter J.
      • Hess R.
      Ultrastructural and biochemical study of the action of benzoctamine and maprotiline on the rat liver.
      Agents Actions. 1974; 4: 391-403
      )
      Mebeverine4-{ethyl[1-(4-methoxyphenyl)propan-2-yl]amino}butyl 3,4-dimethoxybenzoate2743-45-9Anti-diarrheal4.610.31127++417Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      )
      Memantine3,5-Dimethyl-1-adamantanamine hydrochloride41100-52-1NMDA receptor antagonist3.3210.7125++35.7Yes(
      • Morelli J.K.
      • Buehrle M.
      • Pognan F.
      • Barone L.R.
      • Fieles W.
      • Ciaccio P.J.
      Validation of an in vitro screen for phospholipidosis using a high-content biology platform.
      Cell Biol. Toxicol. 2006; 22: 15-27
      ,
      • Shahane S.A.
      • Huang R.
      • Gerhold D.
      • Baxa U.
      • Austin C.P.
      • Xia M.
      Detection of phospholipidosis induction: a cell-based assay in high-throughput and high-content format.
      J. Biomol. Screen. 2014; 19: 66-76
      ,
      • Park S.
      • Choi Y.J.
      • Lee B.H.
      In vitro validation of drug-induced phospholipidosis.
      J. Toxicol. Sci. 2012; 37: 261-267
      ,
      • Honegger U.E.
      • Quack G.
      • Wiesmann U.N.
      Evidence for lysosomotropism of memantine in cultured human cells: cellular kinetics and effects of memantine on phospholipid content and composition, membrane fluidity and beta-adrenergic transmission.
      Pharmacol. Toxicol. 1993; 73: 202-208
      )
      MethapyrileneN-[2-(dimethyl amino)ethyl]-N-[(thiophen-2-yl) methyl ]pyridin-2-amine91-80-5Antihistamine2.878.8586.6-+NDYes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      )
      Mianserin5-methyl-2,5 diazatetracyclo [13.4.0.02,7.08,1³] nonadeca-1(19),8,10,12,15,17-hexaene24219-97-4Antidepressant3.526.960.3-+29.98Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Gonzalez-Rothi R.J.
      • Hannan S.E.
      • Hood C.I.
      • Franzini D.A.
      Amiodarone pulmonary toxicity presenting as bilateral exudative pleural effusions.
      Chest. 1987; 92: 179-182
      ,
      • Hanumegowda U.M.
      • Wenke G.
      • Regueiro-Ren A.
      • Yordanova R.
      • Corradi J.P.
      • Adams S.P.
      Phospholipidosis as a function of basicity, lipophilicity, and volume of distribution of compounds.
      Chem. Res. Toxicol. 2010; 23: 749-755
      )
      Mifepristone(1S,3aS,3bS,10R,11aS)-10-[4-(dimethylamino )phenyl]-1-hydroxy-11a-methyl-1-(prop-1-yn-1-yl)-1H,2H,3H,3aH, 3bH,4H,5H,7H,8H, 9H,10H,11H,11aH-cyclopenta[a]phenanthren-7-one84371-65-3Progesterone blocker5.34.8952+-27.69Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      )
      Mirtazapine5-methyl-2,5,19-triazatetracyclo [13.4.0.02,7.08,1³] nonadeca-1(15),8,10,12,16,18-hexaene85650-52-8Antidepressant2.96.6752.9-+8.7Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Telles-Correia D.
      • Barbosa A.
      • Cortez-Pinto H.
      • Campos C.
      • Rocha N.B.
      • Machado S.
      Psychotropic drugs and liver disease: a critical review of pharmacokinetics and liver toxicity.
      World J. Gastrointest. Pharmacol. Ther. 2017; 8: 26-38
      ,
      • Murakami M.
      • Sato H.
      • Miki Y.
      • Yamamoto K.
      • Taketomi Y.
      A new era of secreted phospholipase A(2).
      J. Lipid Res. 2015; 56: 1248-1261
      )
      Mitotane1-chloro-4-[2,2-dichloro-1-(2-chlorophenyl) ethyl] benzene53-19-0Chemotherapy636--132.1Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Waszut U.
      • Szyszka P.
      • Dworakowska D.
      Understanding mitotane mode of action.
      J. Physiol. Pharmacol. 2017; 68: 13-26
      )
      Naphazoline2-(naphthalen-1-ylmethyl)-4,5-dihydro-1H-imidazole835-31-4Sympathomimetic3.4410.19115++6.98Yes(
      • Morelli J.K.
      • Buehrle M.
      • Pognan F.
      • Barone L.R.
      • Fieles W.
      • Ciaccio P.J.
      Validation of an in vitro screen for phospholipidosis using a high-content biology platform.
      Cell Biol. Toxicol. 2006; 22: 15-27
      )
      Oxolamine citratediethyl[2-(3-phenyl-1,2,4-oxadiazol-5-yl)ethyl]amine959-14-8Anti-psychotic2.78.9687.6-+369Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Kirilmaz L.
      • Kendirci A.
      • Guneri T.
      Sustained-release dosage form of oxolamine citrate: preparation and release kinetics.
      J. Microencapsul. 1992; 9: 167-172
      )
      Oxybutyninα-phenylcyclohexaneglycolic acid 4-(diethyl amino)-2-butynyl ster hydrochloride1508-65-2Anticholinergic4.368.7795.9++26.39Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      )
      Pantoprazole6-(difluoromethoxy)-2-[(3,4-dimethoxypyridin-2-yl) methanesulfinyl] -1H-1,3-benzodiazole102625-70-7Proton pump inhibitor2.113.5517.1--6.23Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Morelli J.K.
      • Buehrle M.
      • Pognan F.
      • Barone L.R.
      • Fieles W.
      • Ciaccio P.J.
      Validation of an in vitro screen for phospholipidosis using a high-content biology platform.
      Cell Biol. Toxicol. 2006; 22: 15-27
      ,
      • Pintavorn P.
      • Cook W.J.
      Progressive renal insufficiency associated with amiodarone-induced phospholipidosis.
      Kidney Int. 2008; 74: 1354-1357
      )
      Paroxetine(3S,4R)-3-[(2H-1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine61869-08-7Antidepressant3.19.77105++5.12R(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Hanumegowda U.M.
      • Wenke G.
      • Regueiro-Ren A.
      • Yordanova R.
      • Corradi J.P.
      • Adams S.P.
      Phospholipidosis as a function of basicity, lipophilicity, and volume of distribution of compounds.
      Chem. Res. Toxicol. 2010; 23: 749-755
      ,
      • Shahane S.A.
      • Huang R.
      • Gerhold D.
      • Baxa U.
      • Austin C.P.
      • Xia M.
      Detection of phospholipidosis induction: a cell-based assay in high-throughput and high-content format.
      J. Biomol. Screen. 2014; 19: 66-76
      ,
      • Kazmi F.
      • Hensley T.
      • Pope C.
      • Funk R.S.
      • Loewen G.J.
      • Buckley D.B.
      • Parkinson A.
      Lysosomal sequestration (trapping) of lipophilic amine (cationic amphiphilic) drugs in immortalized human hepatocytes (Fa2N-4 cells).
      Drug Metab. Dispos. 2013; 41: 897-905
      )
      Penfluridol1-[4,4-bis(4-fluorophenyl)butyl]-4-[4-chloro-3-(trifluoromethyl) phenyl]piperidin-4-ol26864-56-2Antipsychotic6.098.96117-+9.09Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Hanumegowda U.M.
      • Wenke G.
      • Regueiro-Ren A.
      • Yordanova R.
      • Corradi J.P.
      • Adams S.P.
      Phospholipidosis as a function of basicity, lipophilicity, and volume of distribution of compounds.
      Chem. Res. Toxicol. 2010; 23: 749-755
      ,
      • Kornhuber J.
      • Tripal P.
      • Gulbins E.
      • Muehlbacher M.
      Functional inhibitors of acid sphingomyelinase (FIASMAs).
      Handb. Exp. Pharmacol. 2013; : 169-186
      )
      Perhexiline2-(2,2-dicyclohexylethyl) piperidine6621-47-2Coronary vasodilator6.210.58150++11.72YesH,R,M(
      • Sawada H.
      • Takami K.
      • Asahi S.
      A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system.
      Toxicol. Sci. 2005; 83: 282-292
      ,
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Fischer H.
      • Atzpodien E.A.
      • Csato M.
      • Doessegger L.
      • Lenz B.
      • Schmitt G.
      • Singer T.
      In silico assay for assessing phospholipidosis potential of small druglike molecules: training, validation, and refinement using several data sets.
      J. Med. Chem. 2012; 55: 126-139
      ,
      • Morelli J.K.
      • Buehrle M.
      • Pognan F.
      • Barone L.R.
      • Fieles W.
      • Ciaccio P.J.
      Validation of an in vitro screen for phospholipidosis using a high-content biology platform.
      Cell Biol. Toxicol. 2006; 22: 15-27
      ,
      • Hanumegowda U.M.
      • Wenke G.
      • Regueiro-Ren A.
      • Yordanova R.
      • Corradi J.P.
      • Adams S.P.
      Phospholipidosis as a function of basicity, lipophilicity, and volume of distribution of compounds.
      Chem. Res. Toxicol. 2010; 23: 749-755
      ,
      • Przybylak K.R.
      • Cronin M.T.
      In silico studies of the relationship between chemical structure and drug induced phospholipidosis.
      Mol. Inform. 2011; 30: 415-429
      ,
      • Fardeau M.
      • Tome F.M.
      • Simon P.
      Muscle and nerve changes induced by perhexiline maleate in man and mice.
      Muscle Nerve. 1979; 2: 24-36
      ,
      • Lullmann H.
      • Lullmann-Rauch R.
      Perhexiline induces generalized lipidosis in rats.
      Klin. Wochenschr. 1978; 56: 309-310
      ,
      • Lullmann H.
      • Lullmann-Rauch R.
      • Wassermann O.
      Lipidosis induced by amphiphilic cationic drugs.
      Biochem. Pharmacol. 1978; 27: 1103-1108
      )
      Perphenazine2-{4-[3-(2-chloro-10H-phenothiazin-10-yl)propyl] piperazin-1-yl ethan-1-ol58-39-9Antipsychotic4.28.2185-+3.92Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      )
      PhenacetinN-(4-ethoxyphenyl) acetamide62-44-2Non-steroidal1.58-4.22.5--2140YesR(
      • Hurwitz R.
      • Ferlinz K.
      • Sandhoff K.
      The tricyclic antidepressant desipramine causes proteolytic degradation of lysosomal sphingomyelinase in human fibroblasts.
      Biol. Chem. Hoppe Seyler. 1994; 375: 447-450
      ,
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Przybylak K.R.
      • Cronin M.T.
      In silico studies of the relationship between chemical structure and drug induced phospholipidosis.
      Mol. Inform. 2011; 30: 415-429
      ,
      • Zheng N.
      • Zhang X.
      • Rosania G.R.
      Effect of phospholipidosis on the cellular pharmacokinetics of chloroquine.
      J. Pharmacol. Exp. Ther. 2011; 336: 661-671
      ,
      • Pakuts A.P.
      • Parks R.J.
      • Paul C.J.
      • Bujaki S.J.
      • Mueller R.W.
      Ketoconazole-induced hepatic lysosomal phospholipidosis: the effect of concurrent barbiturate treatment.
      Res. Commun. Chem. Pathol. Pharmacol. 1990; 67: 55-62
      )
      Pimozide1-{1-[4,4-bis(4-fluorophenyl)butyl]piperidin-4-yl}-2,3-dihydro-1H-1,3-benzodiazol-2-one2062-78-4Antipsychotic6.368.38111++10.6Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Gonzalez-Rothi R.J.
      • Zander D.S.
      • Ros P.R.
      Fluoxetine hydrochloride (Prozac)-induced pulmonary disease.
      Chest. 1995; 107: 1763-1765
      )
      Pirenperone3-[2-[4-(4-Fluorobenzoyl)-1-piperidinyl]ethyl]-2-methyl-4H-pyrido-[1,2-a] pyrimidin-4-one75444-65-4Antipsychotic2.68.0271.1-+232.6Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Schlecht U.
      • St Onge R.P.
      • Walther T.
      • Francois J.M.
      • Davis R.W.
      Cationic amphiphilic drugs are potent inhibitors of yeast sporulation.
      PLoS One. 2012; 7e42853
      )
      PranlukastN-[4-oxo-2-(2H-1,2,3,4-tetrazol-5-yl)-4H-chromen-8-yl]-4-(4-phenylbutoxy)benzamide103177-37-3Antiasthmatic4.82-1.723.2--NDYes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Kornhuber J.
      • Muehlbacher M.
      • Trapp S.
      • Pechmann S.
      • Friedl A.
      • Reichel M.
      • Mühle C.
      • Terfloth L.
      • Groemer T.W.
      • Spitzer G.M.
      • Liedl K.R.
      • Gulbins E.
      • Tripal P.
      Identification of novel functional inhibitors of acid sphingomyelinase.
      PLoS One. 2011; 6e23852
      )
      Pridinol1,1-diphenyl-3-(piperidin-1-yl)propan-1-ol511-45-5Muscle relaxant3.699.34101++285.4Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Chapy H.
      • Goracci L.
      • Vayer P.
      • Parmentier Y.
      • Carrupt P.A.
      • Decleves X.
      • Scherrmann J.M.
      • Cisternino S.
      • Cruciani G.
      Pharmacophore-based discovery of inhibitors of a novel drug/proton antiporter in human brain endothelial hCMEC/D3 cell line.
      Br. J. Pharmacol. 2015; 172: 4888-4904
      )
      Profenaminediethyl[1-(10H-phenothiazin-10-yl)propan-2-yl]amine522-00-9Antidyskinetic5.759.6125++8.7Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Folts C.J.
      • Scott-Hewitt N.
      • Proschel C.
      • Mayer-Proschel M.
      • Noble M.
      Lysosomal re-acidification prevents lysosphingolipid-induced lysosomal impairment and cellular toxicity.
      PLoS Biol. 2016; 14e1002583
      )
      Progesterone(1S,3aS,3bS,9aR,9bS,11aS)-1-acetyl-9a,11a-dimethyl-1H,2H,3H, 3aH,3bH,4H,5H, 7H,8H,9H,9 aH,9bH, 10H,11H,11aH-cyclopenta [a] phenanthren-7-one57-83-0Hormone3.58-4.812.8--10.52Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Vejux A.
      • Malvitte L.
      • Lizard G.
      Side effects of oxysterols: cytotoxicity, oxidation, inflammation, and phospholipidosis.
      Braz. J. Med. Biol. Res. 2008; 41: 545-556
      )
      Promazinedimethyl[3-(10H-phenothiazin-10-yl)propyl]amine58-40-2Antipsychotic4.559.2105++39YesR(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Fischer H.
      • Atzpodien E.A.
      • Csato M.
      • Doessegger L.
      • Lenz B.
      • Schmitt G.
      • Singer T.
      In silico assay for assessing phospholipidosis potential of small druglike molecules: training, validation, and refinement using several data sets.
      J. Med. Chem. 2012; 55: 126-139
      ,
      • Morelli J.K.
      • Buehrle M.
      • Pognan F.
      • Barone L.R.
      • Fieles W.
      • Ciaccio P.J.
      Validation of an in vitro screen for phospholipidosis using a high-content biology platform.
      Cell Biol. Toxicol. 2006; 22: 15-27
      ,
      • Przybylak K.R.
      • Cronin M.T.
      In silico studies of the relationship between chemical structure and drug induced phospholipidosis.
      Mol. Inform. 2011; 30: 415-429
      )
      Promethazinedimethyl[1-(10H-phenothiazin-10-yl)propan-2-yl] amine60-87-7Antihistamine4.819.05105++40.3YesYes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Shahane S.A.
      • Huang R.
      • Gerhold D.
      • Baxa U.
      • Austin C.P.
      • Xia M.
      Detection of phospholipidosis induction: a cell-based assay in high-throughput and high-content format.
      J. Biomol. Screen. 2014; 19: 66-76
      ,
      • Przybylak K.R.
      • Cronin M.T.
      In silico studies of the relationship between chemical structure and drug induced phospholipidosis.
      Mol. Inform. 2011; 30: 415-429
      )
      Propafenone1-{2-[2-hydroxy-3-(propylamino)propoxy]phenyl}-3-phenylpropan-1-one54063-53-5Antiarrhythmic3.19.63102++48.22Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Slavov S.H.
      • Wilkes J.G.
      • Buzatu D.A.
      • Kruhlak N.L.
      • Willard J.M.
      • Hanig J.P.
      • Beger R.D.
      Computational identification of a phospholipidosis toxicophore using (13)C and (15)N NMR-distance based fingerprints.
      Bioorg. Med. Chem. 2014; 22: 6706-6714
      )
      Proparacaine2-(diethylamino)ethyl 3-amino-4-propoxybenzoate499-67-2Anesthetic2.58.5679.5-+2469Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Xu L.
      • Sheflin L.G.
      • Porter N.A.
      • Fliesler S.J.
      7-Dehydrocholesterol-derived oxysterols and retinal degeneration in a rat model of Smith-Lemli-Opitz syndrome.
      Biochim. Biophys. Acta. 2012; 1821: 877-883
      )
      Propranolol1-(naphthalen-1-yloxy)-3-[(propan-2-yl)amino]propan-2-ol525-66-6Antihypertensive3.489.67106++49.9Yes(
      • Anderson N.
      • Borlak J.
      Drug-induced phospholipidosis.
      FEBS Lett. 2006; 580: 5533-5540
      ,
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Fischer H.
      • Atzpodien E.A.
      • Csato M.
      • Doessegger L.
      • Lenz B.
      • Schmitt G.
      • Singer T.
      In silico assay for assessing phospholipidosis potential of small druglike molecules: training, validation, and refinement using several data sets.
      J. Med. Chem. 2012; 55: 126-139
      ,
      • Morelli J.K.
      • Buehrle M.
      • Pognan F.
      • Barone L.R.
      • Fieles W.
      • Ciaccio P.J.
      Validation of an in vitro screen for phospholipidosis using a high-content biology platform.
      Cell Biol. Toxicol. 2006; 22: 15-27
      ,
      • Hanumegowda U.M.
      • Wenke G.
      • Regueiro-Ren A.
      • Yordanova R.
      • Corradi J.P.
      • Adams S.P.
      Phospholipidosis as a function of basicity, lipophilicity, and volume of distribution of compounds.
      Chem. Res. Toxicol. 2010; 23: 749-755
      ,
      • Shahane S.A.
      • Huang R.
      • Gerhold D.
      • Baxa U.
      • Austin C.P.
      • Xia M.
      Detection of phospholipidosis induction: a cell-based assay in high-throughput and high-content format.
      J. Biomol. Screen. 2014; 19: 66-76
      ,
      • Przybylak K.R.
      • Cronin M.T.
      In silico studies of the relationship between chemical structure and drug induced phospholipidosis.
      Mol. Inform. 2011; 30: 415-429
      )
      PyrilamineN-[2-(dimethyl amino)ethyl]-N-[(4-methoxyphenyl) methyl]pyridin-2-amine91-84-9Antihistamine3.278.7687.4-+214Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Hruban Z.
      Pulmonary and generalized lysosomal storage induced by amphiphilic drugs.
      Environ. Health Perspect. 1984; 55: 53-76
      )
      Quinacrine6- chloro-9-(4-diethylamino-1-methylbutylamino)-2-methoxyacridine dihydrochloride69-05-6Antimalarial and antibiotic5.510.33137++30.13YesR(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Fischer H.
      • Atzpodien E.A.
      • Csato M.
      • Doessegger L.
      • Lenz B.
      • Schmitt G.
      • Singer T.
      In silico assay for assessing phospholipidosis potential of small druglike molecules: training, validation, and refinement using several data sets.
      J. Med. Chem. 2012; 55: 126-139
      ,
      • Morelli J.K.
      • Buehrle M.
      • Pognan F.
      • Barone L.R.
      • Fieles W.
      • Ciaccio P.J.
      Validation of an in vitro screen for phospholipidosis using a high-content biology platform.
      Cell Biol. Toxicol. 2006; 22: 15-27
      ,
      • Hanumegowda U.M.
      • Wenke G.
      • Regueiro-Ren A.
      • Yordanova R.
      • Corradi J.P.
      • Adams S.P.
      Phospholipidosis as a function of basicity, lipophilicity, and volume of distribution of compounds.
      Chem. Res. Toxicol. 2010; 23: 749-755
      ,
      • Shahane S.A.
      • Huang R.
      • Gerhold D.
      • Baxa U.
      • Austin C.P.
      • Xia M.
      Detection of phospholipidosis induction: a cell-based assay in high-throughput and high-content format.
      J. Biomol. Screen. 2014; 19: 66-76
      ,
      • Przybylak K.R.
      • Cronin M.T.
      In silico studies of the relationship between chemical structure and drug induced phospholipidosis.
      Mol. Inform. 2011; 30: 415-429
      ,
      • Zidovetzki R.
      • Sherman I.W.
      • Atiya A.
      • De Boeck H.
      A nuclear magnetic resonance study of the interactions of the antimalarials chloroquine, quinacrine, quinine and mefloquine with dipalmitoylphosphatidylcholine bilayers.
      Mol. Biochem. Parasitol. 1989; 35: 199-207
      )
      Quinine(R)-[(1S,2S,4S,5R)-5-ethenyl-1-azabicyclo [2.2.2]octan-2-yl](6-methoxyquinolin-4-yl)methanol130-95-0Antimalarial3.349.0593.7++164Yes(
      • Hanumegowda U.M.
      • Wenke G.
      • Regueiro-Ren A.
      • Yordanova R.
      • Corradi J.P.
      • Adams S.P.
      Phospholipidosis as a function of basicity, lipophilicity, and volume of distribution of compounds.
      Chem. Res. Toxicol. 2010; 23: 749-755
      ,
      • Przybylak K.R.
      • Cronin M.T.
      In silico studies of the relationship between chemical structure and drug induced phospholipidosis.
      Mol. Inform. 2011; 30: 415-429
      )
      Repaglinide2-ethoxy-4-[2-({3-methyl-1-[2-(1-piperidinyl)phenyl]butyl}amino)-2-oxoethyl]benzoic acid135062-02-1Antihyperglycemic5.94.2853.1-+86.49Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Treyer A.
      • Mateus A.
      • Wisniewski J.R.
      • Boriss H.
      • Matsson P.
      • Artursson P.
      Intracellular drug bioavailability: effect of neutral lipids and phospholipids.
      Mol. Pharm. 2018; 15: 2224-2233
      )
      Retinol(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraen-1-ol68-26-8Vitamin A5.68-2.237.1--52.52Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Song M.
      • Kim Y.J.
      • Ryu J.C.
      Phospholipidosis induced by PPARgamma signaling in human bronchial epithelial (BEAS-2B) cells exposed to amiodarone.
      Toxicol. Sci. 2011; 120: 98-108
      )
      Ropinirole4-[2-(dipropylamino)ethyl]-2,3-dihydro-1H-indol-2-one91374-21-9Dopamine agonist3.0610.17113++NDYes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Rayburn E.R.
      • Gao L.
      • Ding J.
      • Ding H.
      • Shao J.
      • Li H.
      FDA-approved drugs that are spermatotoxic in animals and the utility of animal testing for human risk prediction.
      J. Assist Reprod. Genet. 2018; 35: 191-212
      )
      Sertraline(1S,4S)-4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine79617-96-2Antidepressant5.159.85123+-8.6YesYes(
      • Sawada H.
      • Takami K.
      • Asahi S.
      A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system.
      Toxicol. Sci. 2005; 83: 282-292
      ,
      • Nioi P.
      • Perry B.K.
      • Wang E.J.
      • Gu Y.Z.
      • Snyder R.D.
      In vitro detection of drug-induced phospholipidosis using gene expression and fluorescent phospholipid based methodologies.
      Toxicol. Sci. 2007; 99: 162-173
      ,
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Fischer H.
      • Atzpodien E.A.
      • Csato M.
      • Doessegger L.
      • Lenz B.
      • Schmitt G.
      • Singer T.
      In silico assay for assessing phospholipidosis potential of small druglike molecules: training, validation, and refinement using several data sets.
      J. Med. Chem. 2012; 55: 126-139
      ,
      • Morelli J.K.
      • Buehrle M.
      • Pognan F.
      • Barone L.R.
      • Fieles W.
      • Ciaccio P.J.
      Validation of an in vitro screen for phospholipidosis using a high-content biology platform.
      Cell Biol. Toxicol. 2006; 22: 15-27
      ,
      • Hanumegowda U.M.
      • Wenke G.
      • Regueiro-Ren A.
      • Yordanova R.
      • Corradi J.P.
      • Adams S.P.
      Phospholipidosis as a function of basicity, lipophilicity, and volume of distribution of compounds.
      Chem. Res. Toxicol. 2010; 23: 749-755
      ,
      • Shahane S.A.
      • Huang R.
      • Gerhold D.
      • Baxa U.
      • Austin C.P.
      • Xia M.
      Detection of phospholipidosis induction: a cell-based assay in high-throughput and high-content format.
      J. Biomol. Screen. 2014; 19: 66-76
      ,
      • Przybylak K.R.
      • Cronin M.T.
      In silico studies of the relationship between chemical structure and drug induced phospholipidosis.
      Mol. Inform. 2011; 30: 415-429
      )
      Spiperone8-[3-(p-fluor benzoyl)propyl]-1-phenyl-1,3,8-triazaspiro [4.5]decan-4-one749-02-0Antipsychotic3.038.8988.2-+519.2Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Shahane S.A.
      • Huang R.
      • Gerhold D.
      • Baxa U.
      • Austin C.P.
      • Xia M.
      Detection of phospholipidosis induction: a cell-based assay in high-throughput and high-content format.
      J. Biomol. Screen. 2014; 19: 66-76
      )
      Sulindac2-[(1Z)-5-fluoro-1-[(4-methanesulfinylphenyl)methylidene]-2-methyl-1H-inden-3-yl]acetic acid38194-50-2Nonsteroidal3.42-6.711.7--10.93Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Hanumegowda U.M.
      • Wenke G.
      • Regueiro-Ren A.
      • Yordanova R.
      • Corradi J.P.
      • Adams S.P.
      Phospholipidosis as a function of basicity, lipophilicity, and volume of distribution of compounds.
      Chem. Res. Toxicol. 2010; 23: 749-755
      ,
      • Sahini N.
      • Selvaraj S.
      • Borlak J.
      Whole genome transcript profiling of drug induced steatosis in rats reveals a gene signature predictive of outcome.
      PLoS One. 2014; 9e114085
      )
      SulpirideN-[(1-ethylpyrrolidin-2-yl)methyl]-2-methoxy-5-sulfamoylbenzamide15676-16-1Antidepressant, antipsychotic1.28.471.8--NDYes(
      • Wang T.
      • Feng Y.
      • Jin X.
      • Fan X.
      • Crommen J.
      • Jiang Z.
      Liposome electrokinetic chromatography based in vitro model for early screening of the drug-induced phospholipidosis risk.
      J. Pharm. Biomed. Anal. 2014; 96: 263-271
      )
      Suramin8-{4-methyl-3-[3-({[3-({2-methyl-5-[(4,6,8-trisulfonaphthalen-1yl)carbamoyl]phenyl}carbamoyl)phenyl]carbamoyl}amino)benzamido]benzamido}naphthalene-1,3,5-trisulfonic acid129-46-4Antineoplastic5.58-631.1--35.55YesR(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Soldani P.
      • Pellegrini A.
      • Gesi M.
      • Lenzi P.
      • Paparelli A.
      Suramin-induced ultrastructural changes in the testis of albino rats.
      Exp. Toxicol. Pathol. 1996; 48: 299-305
      ,
      • Raizman M.B.
      • Hamrah P.
      • Holland E.J.
      • Kim T.
      • Mah F.S.
      • Rapuano C.J.
      • Ulrich R.G.
      Drug-induced corneal epithelial changes.
      Surv. Ophthalmol. 2017; 62: 286-301
      )
      Tacrine1,2,3,4-tetrahydroacridin-9-amine321-64-2Cholinesterase inhibitor2.718.9587.5-+63.5Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      )
      Tamoxifen(2-{4-[(1Z)-1,2-diphenylbut-1-en-1-yl]phenoxy} ethyl) dimethylamine10540-29-1Antiestrogenic5.938.76112++7.7YesR(
      • Sawada H.
      • Takami K.
      • Asahi S.
      A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system.
      Toxicol. Sci. 2005; 83: 282-292
      ,
      • Nioi P.
      • Perry B.K.
      • Wang E.J.
      • Gu Y.Z.
      • Snyder R.D.
      In vitro detection of drug-induced phospholipidosis using gene expression and fluorescent phospholipid based methodologies.
      Toxicol. Sci. 2007; 99: 162-173
      ,
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Fischer H.
      • Atzpodien E.A.
      • Csato M.
      • Doessegger L.
      • Lenz B.
      • Schmitt G.
      • Singer T.
      In silico assay for assessing phospholipidosis potential of small druglike molecules: training, validation, and refinement using several data sets.
      J. Med. Chem. 2012; 55: 126-139
      ,
      • Morelli J.K.
      • Buehrle M.
      • Pognan F.
      • Barone L.R.
      • Fieles W.
      • Ciaccio P.J.
      Validation of an in vitro screen for phospholipidosis using a high-content biology platform.
      Cell Biol. Toxicol. 2006; 22: 15-27
      ,
      • Hanumegowda U.M.
      • Wenke G.
      • Regueiro-Ren A.
      • Yordanova R.
      • Corradi J.P.
      • Adams S.P.
      Phospholipidosis as a function of basicity, lipophilicity, and volume of distribution of compounds.
      Chem. Res. Toxicol. 2010; 23: 749-755
      ,
      • Atienzar F.
      • Gerets H.
      • Dufrane S.
      • Tilmant K.
      • Cornet M.
      • Dhalluin S.
      • Ruty B.
      • Rose G.
      • Canning M.
      Determination of phospholipidosis potential based on gene expression analysis in HepG2 cells.
      Toxicol. Sci. 2007; 96: 101-114
      )
      Tetracaine2-(dimethylamino)ethyl 4-(butylamino)benzoate94-24-6Anaesthetic3.548.4283.4-+333Yes(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      )
      Thioridazine10-[2-(1-methylpiperidin-2-yl)ethyl]-2-(methylsulfanyl) -10H-phenothiazine50-52-2Antipsychotic5.98.93115++38YesR(
      • Sawada H.
      • Takami K.
      • Asahi S.
      A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system.
      Toxicol. Sci. 2005; 83: 282-292
      ,
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934
      ,
      • Hanumegowda U.M.
      • Wenke G.
      • Regueiro-Ren A.
      • Yordanova R.
      • Corradi J.P.
      • Adams S.P.
      Phospholipidosis as a function of basicity, lipophilicity, and volume of distribution of compounds.
      Chem. Res. Toxicol. 2010; 23: 749-755
      ,
      • Przybylak K.R.
      • Cronin M.T.
      In silico studies of the relationship between chemical structure and drug induced phospholipidosis.
      Mol. Inform. 2011; 30: 415-429
      ,
      • Bhandari N.
      • Figueroa D.J.
      • Lawrence J.W.
      • Gerhold D.L.
      Phospholipidosis assay in HepG2 cells and rat or rhesus hepatocytes using phospholipid probe NBD-PE.
      Assay Drug Dev. Technol. 2008; 6: 407-419
      )
      TobramycinO-[3-amino-3-deoxy-α-D-glucopyranosyl-(1→6)]-O-[2,6-diamino-2,3,6-trideoxy-α- D-ribohexopyranosyl-(1→4)]-2-deoxy-D-streptamine32986-56-4Antibiotic-5.89.8130++33.03YesR,H(
      • Muehlbacher M.
      • Tripal P.
      • Roas F.
      • Kornhuber J.
      Identification of drugs inducing phospholipidosis by novel in vitro data.
      ChemMedChem. 2012; 7: 1925-1934