Detection of Distinct Distributions of Acetaminophen and Acetaminophen-Cysteine in Kidneys up to 10 μm Resolution and Identification of a Novel Acetaminophen Metabolite Using an AP-MALDI Imaging Mass Microscope

Abstract

Drug distribution studies in tissue are crucial for understanding the pharmacokinetics and potential toxicity of drugs. Recently, matrix-assisted laser desorption ionization-mass spectrometry imaging (MALDI-MSI) has gained attention for drug distribution studies due to its high sensitivity, label-free nature, and ability to distinguish between parent drugs, their metabolites, and endogenous molecules. Despite these advantages, achieving high spatial resolution in drug imaging is challenging. Importantly, many drugs and metabolites are rarely detectable by conventional vacuum MALDI-MSI because of their poor ionization efficiency. It has been reported that acetaminophen (APAP) and one of its major metabolites, APAP-Cysteine (APAP-CYS), cannot be detected by vacuum MALDI-MSI without derivatization. In this context, we showed the distribution of both APAP and APAP-CYS in kidneys at high spatial resolution (25 and 10 μm) by employing an atmospheric pressure-MALDI imaging mass microscope without derivatization. APAP was highly accumulated in the renal pelvis 1 h after drug administration, while APAP-CYS exhibited characteristic distributions in the outer medulla and renal pelvis at both 30 min and 1 h after administration. Interestingly, cluster-like distributions of APAP and APAP-CYS were observed in the renal pelvis at 10 μm spatial resolution. Additionally, a novel APAP metabolite, tentatively coined as APAP-butyl sulfate (APAP-BS), was identified in the kidney, brain, and liver by combining MSI and tandem MSI. For the first time, our study revealed differential distributions of APAP, APAP-CYS (in kidneys), and APAP-BS (in kidney, brain, and liver) and is believed to enhance the understanding of the pharmacokinetics and potential nephrotoxicity of this drug.

Comparative analyses of adsorbed circulating proteins in the PMMA and PES hemodiafilters in patients on predilution online hemodiafiltration

“…Recently, with technological advances [15,16], analyses of plasma proteins have attracted increased interest. Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) demonstrated that the serum protein profile was quite different between HD patients and control subjects [17].…”

Elucidating Gender-Specific Distribution of Imipramine, Chloroquine, and Their Metabolites in Mice Kidney Tissues through AP-MALDI-MSI

“…MSI encompasses mainly three techniques, which include desorption electrospray ionization-MSI (DESI-MSI), secondary ionization mass spectrometry (SIMS), and matrix-assisted laser desorption-ionization-MSI (MALDI-MSI). Among the three MSI tools, this study opted for AP-MALDI-MSI (iMScope TM QT) because it offers more robust quantitative capabilities and advanced imaging competencies with its high spatial resolution (down to micrometer scale) and wide range of analyzing capabilities [20]. AP-MALDI-MSI stands out for its speed (up to 32 pixels/s), label-free nature, sensitivity, and spatial resolution (25 µm × 25 µm) [21].…”

Low-Temperature Plasma Pretreatment Enhanced Cholesterol Detection in Brain by Desorption Electrospray Ionization-Mass Spectrometry Imaging

“…MSI is an emerging technique to visualize various biomolecules in tissues, organs, or whole body sections. It provides spatial molecular information on analytes without distorting tissue anatomy. , It has been efficiently used in metabolomics, lipidomics, , proteomics, biomarker study, and drug distribution studies in tissues. , Prior to the MSI analysis, analytes need to be ionized in an ionizing source (e.g., primary ions, electrospray, plasma, and laser) . Depending on the ionizing sources, the major MSI techniques are matrix-assisted laser desorption/ionization MSI (MALDI-MSI), secondary ion MSI (SIMS), and desorption electrospray ionization MSI (DESI-MSI) .…”