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Direct demonstration of tissue uptake of an inhaled drug: proof-of-principle study using matrix assisted laser desorption ionization mass spectrometry imaging

Fehniger, Thomas LU ; Végvári, Ákos LU ; Rezeli, Melinda LU ; Prikk, Kaiu; Roos, Peter; Dahlbäck, Magnus; Edula, Goutham; Sepper, Ruth and Marko-Varga, György LU (2011) In Analytical Chemistry 83(21). p.8329-8336
Abstract
Drug therapy is often directed to specific organ and tissue compartments where the mode of action of the compound effects specifically targeted biological processes. However, the direct measurement of drug uptake in terms of a time kinetic and concentrations attained at the local sites has not been readily available as a clinical index for most drugs. A proof-of-principle study was conducted to test the utility of applying MALDI mass spectrometry imaging (MALDI-MSI) to demonstrate the qualitative distribution pattern of a locally administered drug within tissue sites of targeted action. Here we have measured the occurrence of an inhaled bronchodilator, the muscarinic receptor antagonist ipratropium, within human bronchial biopsies obtained... (More)
Drug therapy is often directed to specific organ and tissue compartments where the mode of action of the compound effects specifically targeted biological processes. However, the direct measurement of drug uptake in terms of a time kinetic and concentrations attained at the local sites has not been readily available as a clinical index for most drugs. A proof-of-principle study was conducted to test the utility of applying MALDI mass spectrometry imaging (MALDI-MSI) to demonstrate the qualitative distribution pattern of a locally administered drug within tissue sites of targeted action. Here we have measured the occurrence of an inhaled bronchodilator, the muscarinic receptor antagonist ipratropium, within human bronchial biopsies obtained by fiber optic bronchoscopy shortly after dosing exposure. Cryo-preserved biopsy samples from five subjects being evaluated for airway obstruction or potential tumor development were prepared as thin frozen sections. Samples coated with a MALDI matrix were analyzed by a MALDI LTQ Orbitrap XL mass spectrometer at large (100 μm) and small (30 μm) raster size. Our results demonstrate that ipratropium is rapidly absorbed into the airway wall. Ipratropium parent ion (m/z 332.332) and daughter ions (m/z 166.2 and 290.2) were coincidently partitioned within submucosal spaces containing targeted airway smooth muscle in 4/5 subjects. The signal intensity of ipratropium fragment ions provided estimates that local drug concentrations between 3-80 nM were achieved within the airway wall. To our knowledge, this is the first reported study in man applying MALDI-MSI to demonstrate the localization of a drug administered at therapeutic levels. The study highlights the potential benefit of MALDI-MSI to provide important measurements of drug efficacy in clinical settings. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Clinical drug administration, Ipratropium bromide, bronchial tissue, MALDI-MS Imaging, MALDI LTQ Orbitrap XL
in
Analytical Chemistry
volume
83
issue
21
pages
8329 - 8336
publisher
The American Chemical Society
external identifiers
  • wos:000296225300042
  • scopus:80155167810
ISSN
1520-6882
DOI
10.1021/ac2014349
language
English
LU publication?
yes
id
e1d291e7-3d00-42b9-8376-df34c970e66f (old id 2167284)
date added to LUP
2011-10-19 09:39:59
date last changed
2017-09-17 08:18:28
@article{e1d291e7-3d00-42b9-8376-df34c970e66f,
  abstract     = {Drug therapy is often directed to specific organ and tissue compartments where the mode of action of the compound effects specifically targeted biological processes. However, the direct measurement of drug uptake in terms of a time kinetic and concentrations attained at the local sites has not been readily available as a clinical index for most drugs. A proof-of-principle study was conducted to test the utility of applying MALDI mass spectrometry imaging (MALDI-MSI) to demonstrate the qualitative distribution pattern of a locally administered drug within tissue sites of targeted action. Here we have measured the occurrence of an inhaled bronchodilator, the muscarinic receptor antagonist ipratropium, within human bronchial biopsies obtained by fiber optic bronchoscopy shortly after dosing exposure. Cryo-preserved biopsy samples from five subjects being evaluated for airway obstruction or potential tumor development were prepared as thin frozen sections. Samples coated with a MALDI matrix were analyzed by a MALDI LTQ Orbitrap XL mass spectrometer at large (100 μm) and small (30 μm) raster size. Our results demonstrate that ipratropium is rapidly absorbed into the airway wall. Ipratropium parent ion (m/z 332.332) and daughter ions (m/z 166.2 and 290.2) were coincidently partitioned within submucosal spaces containing targeted airway smooth muscle in 4/5 subjects. The signal intensity of ipratropium fragment ions provided estimates that local drug concentrations between 3-80 nM were achieved within the airway wall. To our knowledge, this is the first reported study in man applying MALDI-MSI to demonstrate the localization of a drug administered at therapeutic levels. The study highlights the potential benefit of MALDI-MSI to provide important measurements of drug efficacy in clinical settings.},
  author       = {Fehniger, Thomas and Végvári, Ákos and Rezeli, Melinda and Prikk, Kaiu and Roos, Peter and Dahlbäck, Magnus and Edula, Goutham and Sepper, Ruth and Marko-Varga, György},
  issn         = {1520-6882},
  keyword      = {Clinical drug administration,Ipratropium bromide,bronchial tissue,MALDI-MS Imaging,MALDI LTQ Orbitrap XL},
  language     = {eng},
  number       = {21},
  pages        = {8329--8336},
  publisher    = {The American Chemical Society},
  series       = {Analytical Chemistry},
  title        = {Direct demonstration of tissue uptake of an inhaled drug: proof-of-principle study using matrix assisted laser desorption ionization mass spectrometry imaging},
  url          = {http://dx.doi.org/10.1021/ac2014349},
  volume       = {83},
  year         = {2011},
}