title: In situ mass spectrometry imaging and ex vivo characterization of renal crystalline deposits induced in multiple preclinical drug toxicology studies.
abstract: Drug toxicity observed in animal studies during drug development accounts for the discontinuation of many drug candidates, with the kidney being a major site of tissue damage. Extensive investigations are often required to reveal the mechanisms underlying such toxicological events and in the case of crystalline deposits the chemical composition can be problematic to determine. In the present study, we have used mass spectrometry imaging combined with a set of advanced analytical techniques to characterize such crystalline deposits in situ. Two potential microsomal prostaglandin E synthase 1 inhibitors, with similar chemical structure, were administered to rats over a seven day period. This resulted in kidney damage with marked tubular degeneration/regeneration and crystal deposits within the tissue that was detected by histopathology. Results from direct tissue section analysis by matrix-assisted laser desorption ionization mass spectrometry imaging were combined with data obtained following manual crystal dissection analyzed by liquid chromatography mass spectrometry and nuclear magnetic resonance spectroscopy. The chemical composition of the crystal deposits was successfully identified as a common metabolite, bisulphonamide, of the two drug candidates. In addition, an un-targeted analysis revealed molecular changes in the kidney that were specifically associated with the area of the tissue defined as pathologically damaged. In the presented study, we show the usefulness of combining mass spectrometry imaging with an array of powerful analytical tools to solve complex toxicological problems occurring during drug development.
authors.affiliation: Medical Mass Spectrometry, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden. anna.nilsson@farmbio.uu.se
authors.forename: Anna
authors.initials: A
authors.lastname: Nilsson
authors.forename: Benita
authors.initials: B
authors.lastname: Forngren
authors.forename: Sivert
authors.initials: S
authors.lastname: Bjurström
authors.forename: Richard J A
authors.initials: RJ
authors.lastname: Goodwin
authors.forename: Elisa
authors.initials: E
authors.lastname: Basmaci
authors.forename: Ingela
authors.initials: I
authors.lastname: Gustafsson
authors.forename: Anita
authors.initials: A
authors.lastname: Annas
authors.forename: Dennis
authors.initials: D
authors.lastname: Hellgren
authors.forename: Alexander
authors.initials: A
authors.lastname: Svanhagen
authors.forename: Per E
authors.initials: PE
authors.lastname: Andrén
authors.forename: Johan
authors.initials: J
authors.lastname: Lindberg
mesh_terms: D000818:Animals; D002853:Chromatography, Liquid; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics; D005260:Female; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors; D007668:Kidney / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry / Q000379:methods*; D000071876:Prostaglandin-E Synthases; D051381:Rats; D014116:Toxicology
chemical_list: D004791:Enzyme Inhibitors; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases