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Investigating Nephrotoxicity of Polymyxin Derivatives by Mapping Renal Distribution Using Mass Spectrometry Imaging
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
AstraZeneca R&D, Drug Safety & Metab, Innovat Med, Cambridge CB4 0WG, England..
AstraZeneca R&D, Drug Safety & Metab, Innovat Med, Cambridge CB4 0WG, England..
AstraZeneca R&D, Oncol DMPK, Innovat Med, Macclesfield SK10 4TF, Cheshire, England..
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2015 (English)In: Chemical Research in Toxicology, ISSN 0893-228X, E-ISSN 1520-5010, Vol. 28, no 9, 1823-1830 p.Article in journal (Refereed) Published
Abstract [en]

Colistin and polymyxin B are effective treatment options for Gram-negative resistant bacteria but are used as last-line therapy due to their dose-limiting nephrotoxicity. A critical factor in developing safer polymyxin analogues is understanding accumulation of the drugs and their metabolites, which is currently limited due to the lack of effective techniques for analysis of these challenging molecules. Mass spectrometry imaging (MSI) allows direct detection of targets (drugs, metabolites, and endogenous compounds) from tissue sections. The presented study exemplifies the utility of MSI by measuring the distribution of polymyxin B1, colistin, and polymyxin B nonapeptide (PMBN) within dosed rat kidney tissue sections. The label-free MSI analysis revealed that the nephrotoxic compounds (polymyxin B1 and colistin) preferentially accumulated in the renal cortical region. The less nephrotoxic analogue, polymyxin B nonapeptide, was more uniformly distributed throughout the kidney. In addition, metabolites of the dosed compounds were detected by MSI. Kidney homogenates were analyzed using LC/MS/MS to determine total drug exposure and for metabolite identification. To our knowledge, this is the first time such techniques have been utilized to measure the distribution of polymyxin drugs and their metabolites. By simultaneously detecting the distribution of drug and drug metabolites, MSI offers a powerful alternative to tissue homogenization analysis and label or antibody-based imaging.

Place, publisher, year, edition, pages
2015. Vol. 28, no 9, 1823-1830 p.
National Category
Pharmacology and Toxicology Chemical Sciences
URN: urn:nbn:se:uu:diva-265618DOI: 10.1021/acs.chemrestox.5b00262ISI: 000361865300019PubMedID: 26293472OAI: oai:DiVA.org:uu-265618DiVA: diva2:867028
AstraZenecaSwedish Research Council, 2008-5597 2013-3105 2014-6215 2009-6050
Available from: 2015-11-04 Created: 2015-11-02 Last updated: 2015-11-04Bibliographically approved

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Nilsson, AnnaAndrén, Per E.
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