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 heathy lung tissue to pirfenidone treatment.
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Abbreviations
- AUC0–∞ :
-
Area under the curve from 0 to infinity
- C max :
-
Maximum concentration
- CASI:
-
Continuous accumulation of selected ions
- CID:
-
Collision-induced dissociation
- CMC:
-
Carboxymethyl cellulose
- FTICR:
-
Fourier transform ion cyclotron resonance
- T 1/2 :
-
Half-life
- IPF:
-
Idiopathic pulmonary fibrosis
- ITO:
-
Indium tin oxide
- LC–MS/MS:
-
Liquid chromatography–tandem mass spectrometry
- MALDI-MSI:
-
Matrix-assisted laser desorption/ionization-mass spectrometry imaging
- Pirfenidone-d5:
-
5-Methyl-N-phenyl-2-1H-pyridone-d5
- t max :
-
Time to maximum concentration
- 9-AA:
-
9-Aminoacridine
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Acknowledgments
The authors would like to thank Claudia-Marieke Pflüger, Ulrike Buchholz, Gabriele Mettenleiter and Andreas Voss from the Research Unit Analytical Pathology, Constanze Heise and Daniela Dietel from the Comprehensive Pneumology Center, and Xiaomeng Wan from the University of North Carolina at Chapel Hill for providing technical assistance. We thank Alice Ly from the Research Unit Analytical Pathology for proofreading our manuscript.
Funding sources
The study was supported by Helmholtz Zentrum München (TKP-Project), the German Center for Lung Research (DZL), the Ministry of Education and Research of the Federal Republic of Germany (BMBF) (01ZX1310B and 01IB10004E) and the Deutsche Forschungsgemeinschaft (SFB 824 TP Z02 and H01258/3-1).
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Oliver Eickelberg and Axel Walch have contributed equally to this work.
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Sun, N., Fernandez, I.E., Wei, M. et al. Pharmacokinetic and pharmacometabolomic study of pirfenidone in normal mouse tissues using high mass resolution MALDI-FTICR-mass spectrometry imaging. Histochem Cell Biol 145, 201–211 (2016). https://doi.org/10.1007/s00418-015-1382-7
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DOI: https://doi.org/10.1007/s00418-015-1382-7