title: Pharmacokinetic and pharmacometabolomic study of pirfenidone in normal mouse tissues using high mass resolution MALDI-FTICR-mass spectrometry imaging.
abstract: Given the importance of pirfenidone as the first worldwide-approved drug for idiopathic pulmonary fibrosis treatment, its pharmacodynamic properties and the metabolic response to pirfenidone treatment have not been fully elucidated. The aim of the present study was to get molecular insights of pirfenidone-related pharmacometabolomic response using MALDI-FTICR-MSI. Quantitative MALDI-FTICR-MSI was carried out for determining the pharmacokinetic properties of pirfenidone and its related metabolites 5-hydroxymethyl pirfenidone and 5-carboxy pirfenidone in lung, liver and kidney. To monitor the effect of pirfenidone administration on endogenous cell metabolism, additional in situ endogenous metabolite imaging was performed in lung tissue sections. While pirfenidone is highly abundant and delocalized across the whole micro-regions of lung, kidney and liver, 5-hydroxymethyl pirfenidone and 5-carboxy pirfenidone demonstrate heterogeneous distribution patterns in lung and kidney. In situ endogenous metabolite imaging study of lung tissue indicates no significant effects of pirfenidone on metabolic pathways. Remarkably, we found 129 discriminative m/z values which represent clear differences between control and treated lungs, the majority of which are currently unknown. PCA analysis and heatmap view can accurately distinguish control and treated groups. This is the first pharmacokinetic study to investigate the tissue distribution of orally administered pirfenidone and its related metabolites simultaneously in organs without labeling. The combination of pharmametabolome with histological features provides detailed mapping of drug effects on metabolism as response of healthy lung tissue to pirfenidone treatment.
authors.affiliation: Research Unit Analytical Pathology, German Research Center for Environmental Health (GmbH), Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Na
authors.initials: N
authors.lastname: Sun
authors.affiliation: Comprehensive Pneumology Center, German Center for Lung Research (DZL), Ludwig Maximilian University München, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Isis E
authors.initials: IE
authors.lastname: Fernandez
authors.affiliation: Research Unit Analytical Pathology, German Research Center for Environmental Health (GmbH), Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Mian
authors.initials: M
authors.lastname: Wei
authors.affiliation: Research Unit Analytical Pathology, German Research Center for Environmental Health (GmbH), Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Yin
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Research Unit Analytical Pathology, German Research Center for Environmental Health (GmbH), Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Aichler
authors.affiliation: Comprehensive Pneumology Center, German Center for Lung Research (DZL), Ludwig Maximilian University München, Helmholtz Zentrum München, Neuherberg, Germany. oliver.eickelberg@helmholtz-muenchen.de.
authors.forename: Oliver
authors.initials: O
authors.lastname: Eickelberg
authors.affiliation: Research Unit Analytical Pathology, German Research Center for Environmental Health (GmbH), Helmholtz Zentrum München, Neuherberg, Germany. axel.walch@helmholtz-muenchen.de.
authors.forename: Axel
authors.initials: A
authors.lastname: Walch
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000032:analysis / Q000378:metabolism* / Q000493:pharmacokinetics*; D005260:Female; D007668:Kidney / Q000737:chemistry / Q000378:metabolism; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D008168:Lung / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011728:Pyridones / Q000032:analysis / Q000378:metabolism* / Q000493:pharmacokinetics*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014018:Tissue Distribution
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D011728:Pyridones; C093844:pirfenidone
keywords: 5-Carboxy pirfenidone; 5-Hydroxymethyl pirfenidone; Idiopathic pulmonary fibrosis; Mass spectrometry imaging; Pharmacokinetics; Pharmacometabolomics; Pirfenidone