title: Comparison of the diagnostic accuracy of di-22:6-bis(monoacylglycerol)phosphate and other urinary phospholipids for drug-induced phospholipidosis or tissue injury in the rat.
abstract: Cationic amphiphilic drugs and aminoglycoside antibiotics can induce phospholipidosis (PLD), an abnormal accumulation of phospholipids in lysosome-derived vesicles, in preclinical studies. The incidence of PLD in patients and its clinical relevance are difficult to assess without noninvasive biomarkers. Di-docosahexaenoyl bis(monoacylglycerol)phosphate (di-22:6-BMP) is a phospholipid that is enriched in lysosomal membranes and a proposed urinary biomarker of drug-induced PLD. The specificity of di-22:6-BMP for PLD was compared to other phospholipid species that can increase in urine with nephrotoxicity. Using liquid chromatography coupled to mass spectrometry, 12 phospholipids were assayed in the urine of rats treated with drugs that induced PLD or caused renal or skeletal muscle injury. In receiver operating curve analyses, urinary di-22:6-BMP was a significantly better predictor of PLD and the least predictive of tissue injury of the phospholipids assayed. The data provide evidence supporting the use of di-22:6-BMP as a urinary biomarker of PLD in rats.
authors.affiliation: Center for Drug Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Avenue, Building 64, Room 2036, Silver Spring, MD 20993, USA. karol.thompson@fda.hhs.gov
authors.forename: Karol L
authors.initials: KL
authors.lastname: Thompson
authors.forename: Kylie
authors.initials: K
authors.lastname: Haskins
authors.forename: Barry A
authors.initials: BA
authors.lastname: Rosenzweig
authors.forename: Sharron
authors.initials: S
authors.lastname: Stewart
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: David
authors.initials: D
authors.lastname: Peters
authors.forename: Alan
authors.initials: A
authors.lastname: Knapton
authors.forename: Rodney
authors.initials: R
authors.lastname: Rouse
authors.forename: Daniel
authors.initials: D
authors.lastname: Mans
authors.forename: Thomas
authors.initials: T
authors.lastname: Colatsky
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000652:urine; D015815:Cell Adhesion Molecules / Q000652:urine; D002945:Cisplatin / Q000009:adverse effects; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005839:Gentamicins / Q000009:adverse effects; D006589:Hexestrol / Q000009:adverse effects / Q000031:analogs & derivatives; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology / Q000652:urine; D000071068:Lipocalin-2; D054834:Lipocalins / Q000652:urine; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008198:Lymph Nodes / Q000187:drug effects / Q000473:pathology; D008246:Lysophospholipids / Q000652:urine*; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053495:Osteopontin / Q000652:urine; D010743:Phospholipids / Q000652:urine*; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000009:adverse effects; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D019210:Troponin I / Q000097:blood
chemical_list: D015415:Biomarkers; D015815:Cell Adhesion Molecules; D002945:Cisplatin; D005839:Gentamicins; D006589:Hexestrol; D000071068:Lipocalin-2; D054834:Lipocalins; D008246:Lysophospholipids; D053495:Osteopontin; D010743:Phospholipids; D019821:Simvastatin; D019210:Troponin I; C110936:Havcr1 protein, rat; C097278:Lcn2 protein, rat; C517624:didocosahexaenoyl bis(monoacylglycerol) phosphate; C100116:hexestrol bis(diethylaminoethyl ether)