title: Investigating nephrotoxicity of polymyxin derivatives by mapping renal distribution using mass spectrometry imaging.
abstract: 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.
authors: Biomolecular Imaging and Proteomics, National Center for Mass Spectrometry Imaging, Department of Pharmaceutical Biosciences, Uppsala University , Uppsala SE-75237, Sweden.
authors: Anna
authors: A
authors: Nilsson
authors: Drug Safety & Metabolism, Innovative Medicines, AstraZeneca R&D , Cambridge CB4 OWG, U.K.
authors: Richard J A
authors: RJ
authors: Goodwin
authors: Drug Safety & Metabolism, Innovative Medicines, AstraZeneca R&D , Cambridge CB4 OWG, U.K.
authors: John G
authors: JG
authors: Swales
authors: Oncology DMPK, Innovative Medicines, AstraZeneca R&D , Alderley Park, Macclesfield SK10 4TF, U.K.
authors: Richard
authors: R
authors: Gallagher
authors: Drug Safety & Metabolism, Innovative Medicines, AstraZeneca R&D , Waltham, Massachusetts 02451, United States.
authors: Harish
authors: H
authors: Shankaran
authors: Infection DMPK, Innovative Medicines, AstraZeneca R&D , Waltham, Massachusetts 02451, United States.
authors: Abhishek
authors: A
authors: Sathe
authors: Infection DMPK, Innovative Medicines, AstraZeneca R&D , Waltham, Massachusetts 02451, United States.
authors: Selvi
authors: S
authors: Pradeepan
authors: Drug Safety & Metabolism, Innovative Medicines, AstraZeneca R&D , Waltham, Massachusetts 02451, United States.
authors: Aixiang
authors: A
authors: Xue
authors: Drug Safety & Metabolism, Innovative Medicines, AstraZeneca R&D , Waltham, Massachusetts 02451, United States.
authors: Natalie
authors: N
authors: Keirstead
authors: Drug Safety & Metabolism, Innovative Medicines, AstraZeneca R&D , Waltham, Massachusetts 02451, United States.
authors: Jennifer C
authors: JC
authors: Sasaki
authors: Biomolecular Imaging and Proteomics, National Center for Mass Spectrometry Imaging, Department of Pharmaceutical Biosciences, Uppsala University , Uppsala SE-75237, Sweden.
authors: Per E
authors: PE
authors: Andren
authors: Infection DMPK, Innovative Medicines, AstraZeneca R&D , Waltham, Massachusetts 02451, United States.
authors: Anshul
authors: A
authors: Gupta
mesh_terms: D000818:Animals; D002853:Chromatography, Liquid; D007668:Kidney / Q000187:drug effects*; D008297:Male; D011113:Polymyxins / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*
chemical_list: D011113:Polymyxins