Mass Spectrometry Imaging of Diclofenac and Its Metabolites in Tissues Using Nanospray Desorption Electrospray Ionization.
2020
Glucuronidation is a common phase II metabolic process for
drugs and xenobiotics which increases their solubility for excretion. Acyl glucuronides
(glucuronides of carboxylic acids) present concerns of toxicity as they have
been implicated in gastrointestinal toxicity and hepatic failure. Despite the
substantial success in the bulk analysis of these species, little is known
about their localization in tissues. Herein,
we used nanospray desorption electrospray ionization mass spectrometry imaging
(nano-DESI-MSI) to examine the localization of diclofenac, a
widely used nonsteroidal anti-inflammatory drug, and its metabolites in mouse kidney and liver
tissues. Nano-DESI allows for label-free imaging with high spatial resolution and
sensitivity without special sample pretreatment. Using nano-DESI-MSI, ion
images for diclofenac and its major metabolites were produced. MSI data
acquired over a broad m/z range
showed fairly low signals of the drug and its metabolites. At least an order of
magnitude improvement in the signals was obtained using selected ion monitoring
(SIM), with m/z windows centered
around the low-abundance ions of interest. Using nano-DESI MSI in SIM mode, we
observed that diclofenac acyl glucuronide is localized to the inner medulla and
hydroxydiclofenac to the cortex of the kidney. The distributions observed for
both metabolites closely match the previously reported localization of enzymes
that process diclofenac into its respective metabolites. The localization of diclofenac
acyl glucuronide to medulla likely indicates that the toxic metabolite is being
excreted from the tissue. In contrast, a
uniform distribution of diclofenac, hydroxydiclofenac and the diclofenac acyl glucuronide
metabolite was observed in the liver tissue. Semiquantitative analysis found the
metabolite to diclofenac ratios calculated from nano-DESI in agreement to those
calculated from liquid chromatography tandem mass spectrometry (LC-MS/MS)
experiments. Collectively, our results demonstrate nano-DESI-MSI can be
successfully used to image diclofenac and its primary metabolites in dosed
liver and kidney tissues from mice and derive semi-quantitative data from
localized tissue regions.
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