Direct analysis of drug candidates in tissue by matrix-assisted laser desorption/ionization mass spectrometry.
Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) has been used to directly analyze and image pharmaceutical compounds in intact tissue. The anti-tumor drug SCH 226374 was unambiguously determined in mouse tumor tissue using MALDI-QqTOFMS (QSTAR) by monitoring the dissociation of the protonated drug at m/z 695.4 to its predominant fragment at m/z 228.1. A second drug, compound A, was detected in slices of rat brain tissue following oral administration with doses ranging from 1-25 mg/kg. Quantitation of compound A from whole brain homogenates using routine high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS) procedures revealed that concentrations of the drug in whole brain varied from a low of 24 ng/g to a high of 1790 ng/g. The drug candidate was successfully detected by MALDI-QqTOF in samples from each dose, covering a range of approximately two orders of magnitude. In addition, good correlation was observed between the MALDI-QqTOFMS intensities at each dose with the HPLC/MS/MS results. Thus the MALDI-MS response is proportional to the amount of drug in tissue. Custom software was developed to facilitate the imaging of small molecules in tissue using the MALDI-QqTOF mass spectrometer. Images revealing the spatial localization of SCH 226374 in tumor tissue and compound A in brain tissue were acquired.
Department of Biochemistry, Mass Spectrometry Research Center, Vanderbilt University, Nashville, TN 37232, USA.
Michelle L
ML
Reyzer
Yunsheng
Y
Hsieh
Kwokei
K
Ng
Walter A
WA
Korfmacher
Richard M
RM
Caprioli
D000818:Animals; D001921:Brain / Q000378:metabolism; D003373:Coumaric Acids / Q000737:chemistry / Q000493:pharmacokinetics; D007093:Imidazoles / Q000737:chemistry / Q000493:pharmacokinetics; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000032:analysis* / Q000737:chemistry; D010879:Piperazines / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D012680:Sensitivity and Specificity; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods*; D014020:Tissue Extracts / Q000737:chemistry*
D003373:Coumaric Acids; D007093:Imidazoles; D004364:Pharmaceutical Preparations; D010879:Piperazines; C480595:SCH 226374; D014020:Tissue Extracts; C073734:sinapinic acid