Matrix-assisted laser desorption/ionization imaging mass spectrometry for direct measurement of clozapine in rat brain tissue

被引:151
作者
Hsieh, Y [1 ]
Casale, R
Fukuda, E
Chen, JW
Knemeyer, I
Wingate, J
Morrison, R
Korfmacher, W
机构
[1] Schering Plough Res Inst, Drug Metab & Pharmacokinet Dept, Kenilworth, NJ 07033 USA
[2] AB MDS Sciex, Concord, ON L4K 4V8, Canada
关键词
D O I
10.1002/rcm.2397
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
Matrix-assisted laser desorption/ionization hyphenated with quadrupole time-of-flight (QTOF) mass spectrometry (MS) has been used to directly determine the distribution of pharmaceuticals in rat brain tissue slices which might unravel their disposition for new drug development. Clozapine, an antipsychotic drug, and norclozapine were used as model compounds to investigate fundamental parameters such as matrix and solvent effects and irradiance dependence on MALDI intensity but also to address the issues with direct tissue imaging MS technique such as (1) uniform coating by the matrix, (2) linearity of MALDI signals, and (3) redistribution of surface analytes. The tissue sections were coated with various matrices on MALDI plates by airspray deposition prior to MS detection. MALDI signals of analytes were detected by monitoring the dissociation of the individual protonated molecules to their predominant MS/MS product ions. The matrices were chosen for tissue applications based on their ability to form a homogeneous coating of dense crystals and to yield greater sensitivity. Images revealing the spatial localization in tissue sections using MALDI-QTOF following a direct infusion of 3 H-clozapine into rat brain were found to be in good correlation with those using a radioautographic approach. The density of clozapine and its major metabolites from whole brain homogenates was further confirmed using fast high-performance liquid chromatography/tandem mass spectrometry (HPLC-MS/MS) procedures. Copyright (c) 2006 John Wiley & Sons, Ltd.
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页码:965 / 972
页数:8
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