Direct Demonstration of Tissue Uptake of an Inhaled Drug: Proof-of-Principle Study Using Matrix-Assisted Laser Desorption Ionization Mass Spectrometry Imaging
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- 作者：Thomas E. Fehniger ; 脕kos V茅gv谩ri ; Melinda Rezeli ; Kaiu Prikk ; Peeter Ross ; Magnus Dahlb盲ck ; Goutham Edula ; Ruth Sepper ; Gy枚rgy Marko-Varga
- 刊名：Analytical Chemistry
- 出版年：2011
- 出版时间：November 1, 2011
- 年：2011
- 卷：83
- 期：21
- 页码：8329-8336
- 全文大小：1086K
- 年卷期：v.83,no.21(November 1, 2011)
- ISSN：1520-6882
文摘
Drug therapy is often directed to specific organ and tissue compartments where the mode of action of the compound affects 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 matrix-assisted laser desorption ionization-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 渭m) and small (30 渭m) raster sizes. 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 four out of five subjects. The signal intensity of ipratropium fragment ions provided estimates that local drug concentrations between 3 and 80 nM were achieved within the airway wall. To our knowledge, this is the first reported study in 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.