title: Metabolomics analysis reveals elevation of 3-indoxyl sulfate in plasma and brain during chemically-induced acute kidney injury in mice: investigation of nicotinic acid receptor agonists.
abstract: An investigative renal toxicity study using metabolomics was conducted with a potent nicotinic acid receptor (NAR) agonist, SCH 900424. Liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) techniques were used to identify small molecule biomarkers of acute kidney injury (AKI) that could aid in a better mechanistic understanding of SCH 900424-induced AKI in mice. The metabolomics study revealed 3-indoxyl sulfate (3IS) as a more sensitive marker of SCH 900424-induced renal toxicity than creatinine or urea. An LC-MS assay for quantitative determination of 3IS in mouse matrices was also developed. Following treatment with SCH 900424, 3IS levels were markedly increased in murine plasma and brain, thereby potentially contributing to renal- and central nervous system (CNS)-related rapid onset of toxicities. Furthermore, significant decrease in urinary excretion of 3IS in those animals due to compromised renal function may be associated with the elevation of 3IS in plasma and brain. These data suggest that 3IS has a potential to be a marker of renal and CNS toxicities during chemically-induced AKI in mice. In addition, based on the metabolomic analysis other statistically significant plasma markers including p-cresol-sulfate and tryptophan catabolites (kynurenate, kynurenine, 3-indole-lactate) might be of toxicological importance but have not been studied in detail. This comprehensive approach that includes untargeted metabolomic and targeted bioanalytical sample analyses could be used to investigate toxicity of other compounds that pose preclinical or clinical development challenges in a pharmaceutical discovery and development.
authors.affiliation: Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, P.O. Box 2000, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA. joanna.pols@merck.com
authors.forename: Joanna R
authors.initials: JR
authors.lastname: Zgoda-Pols
authors.forename: Swapan
authors.initials: S
authors.lastname: Chowdhury
authors.forename: Mark
authors.initials: M
authors.lastname: Wirth
authors.forename: Michael V
authors.initials: MV
authors.lastname: Milburn
authors.forename: Danny C
authors.initials: DC
authors.lastname: Alexander
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Alton
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000378:metabolism; D000818:Animals; D015415:Biomarkers; D001921:Brain / Q000378:metabolism*; D007200:Indican / Q000032:analysis* / Q000097:blood; D007668:Kidney / Q000187:drug effects; D008297:Male; D055432:Metabolomics; D051379:Mice; D018722:Nicotinic Agonists / Q000633:toxicity*; D027362:Organic Anion Transport Protein 1 / Q000502:physiology; D029362:Organic Anion Transporters, Sodium-Independent / Q000502:physiology
chemical_list: D015415:Biomarkers; D018722:Nicotinic Agonists; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; C114338:organic anion transport protein 3; D007200:Indican