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Identification of a Crystalline Drug Metabolite in Tissue Sections using Microscopy and Maldi-MS

Published online by Cambridge University Press:  02 July 2020

J. Fagerland ,
L. Miesbauer ,
R. Burton ,
F. Seiler ,
J. Neilly ,
D. Hickman ,
A. Buko  and
J. Leal
J. Fagerland
Affiliation:
Dept. Microscopy and Microanalysis, Abbott Laboratories, Abbott Park, IL60064-6202
L. Miesbauer
Affiliation:
Dept. Structural Chemistry, Abbott Laboratories, Abbott Park, IL60064
R. Burton
Affiliation:
Dept. Structural Chemistry, Abbott Laboratories, Abbott Park, IL60064
F. Seiler
Affiliation:
Dept. Microscopy and Microanalysis, Abbott Laboratories, Abbott Park, IL60064-6202
J. Neilly
Affiliation:
Dept. Microscopy and Microanalysis, Abbott Laboratories, Abbott Park, IL60064-6202
D. Hickman
Affiliation:
Dept. Metabolism, Radiochemistry, and Cellular Toxicity, Abbott Laboratories, Abbott Park, IL60064
A. Buko
Affiliation:
Dept. Structural Chemistry, Abbott Laboratories, Abbott Park, IL60064
J. Leal
Affiliation:
Dept. Chemotherapeutics, Abbott Laboratories, Abbott Park, IL60064
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Extract

Development of a potential drug candidate was discontinued when rats treated with the compound developed severe renal toxicity after one week of daily dosing. Tubular degeneration in the kidney was accompanied by deposition of large amounts of crystalline material, which was also present in spleen and pancreas (Fig. 1). It was presumed that the crystals were precipitated parent drug or one of its metabolites. Using microscopy and mass spectrometry, it was confirmed that the crystals were indeed derived from the drug and not endogenously formed; in addition, the precise metabolite that had precipitated in the tissues was identified, providing clues to the metabolic pathways involved.

Frozen sections of phosphate-buffered formaldehyde-fixed kidney, pancreas, and spleen were evaluated by polarized light microscopy (PLM), scanning electron microscopy (SEM) with energy dispersive x-ray spectroscopy (EDXS), and matrix assisted laser desorption ionization-mass spectrometry (MALDI-MS). For reference, crystals of the trifluoroacetate salt of the parent drug were also analyzed using these methods.

Type
Microscopy and Microanalysis in the Pharmaceutical Industry
Information
Microscopy and Microanalysis , Volume 6 , Issue S2: Proceedings: Microscopy & Microanalysis 2000, Microscopy Society of America 58th Annual Meeting, Microbeam Analysis Society 34th Annual Meeting, Microscopical Society of Canada/Societe de Microscopie de Canada 27th Annual Meeting, Philadelphia, Pennsylvania August 13-17, 2000 , August 2000 , pp. 1002 - 1003
Copyright
Copyright © Microscopy Society of America

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References

References:

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