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Distribution study of atorvastatin and its metabolites in rat tissues using combined information from UHPLC/MS and MALDI-Orbitrap-MS imaging

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Abstract

The combination of ultrahigh-resolution mass spectrometry imaging (UHRMSI) and ultrahigh-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC/MS/MS) was used for the identification and the spatial localization of atorvastatin (AT) and its metabolites in rat tissues. Ultrahigh-resolution and high mass accuracy measurements on a matrix-assisted laser desorption/ionization (MALDI)-Orbitrap mass spectrometer allowed better detection of desired analytes in the background of matrix and endogenous compounds. Tandem mass spectra were also used to confirm the identification of detected metabolites in complex matrices. The optimization of sample preparation before imaging experiments included the tissue cryogenic sectioning (thickness 20 μm), the transfer to stainless steel or glass slide, and the selection of suitable matrix and its homogenous deposition on the tissue slice. Thirteen matrices typically used for small molecule analysis, e.g., 2,5-dihydroxybenzoic acid (DHB), 1,5-diaminonaphthalene (DAN), 9-aminoacridine (AA), etc., were investigated for the studied drug and its metabolite detection efficiency in both polarity modes. Particular matrices were scored based on the strength of extracted ion current (EIC), relative ratio of AT molecular adducts, and fragment ions. The matrix deposition on the tissue for the most suitable matrices was done by sublimation to obtain the small crystal size and to avoid local variations in the ionization efficiency. UHPLC/MS profiling of drug metabolites in adjacent tissue slices with the previously optimized extraction was performed in parallel to mass spectrometry imaging (MSI) measurements to obtain more detailed information on metabolites in addition to the spatial information from MSI. The quantitation of atorvastatin in rat liver, serum, and feces was also performed.

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Abbreviations

AA:

9-Aminoacridine

AAP:

3-Aminoacetophenone

AP:

2-Aminopyrazine

AQ:

3-Aminoquinoline

AT:

Atorvastatin

BuCHCA:

Butylamine salt of α-cyano-4-hydroxycinnamic acid

CHCA:

α-Cyano-4-hydroxycinnamic acid

CID:

Collision-induced dissociation

DAN:

1,5-Diaminonaphthalene

DHA:

2,6-Dihydroxyacetophenone

DHB:

2,5-Dihydroxybenzoic acid

DMAN:

N,N,N′,N′-tetramethyl-1,8-naphthalenediamine

EIC:

Extracted ion current

ESI:

Electrospray ionization

FD:

Fragmentation degree

HCD:

Higher energy collisional induced dissociation

HPLC:

High-performance liquid chromatography

LOD:

Limit of detection

MALDI:

Matrix-assisted laser desorption/ionization

MBT:

2-Mercaptobenzothiazole

MS:

Mass spectrometry

MSI:

Mass spectrometry imaging

MS/MS:

Tandem mass spectrometry

NaDHB:

Sodium 2,5-dihydroxybenzoate

QTOF:

Quadrupole-time-of-flight

THA:

2,4,6-Trihydroxyacetophenone

UHPLC:

Ultrahigh-performance liquid chromatography

UHPLC/MS/MS:

Ultrahigh-performance liquid chromatography-tandem mass spectrometry

UHRMS:

Ultrahigh-resolution mass spectrometry

UHRMSI:

Ultrahigh-resolution mass spectrometry imaging

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Acknowledgments

This project was supported by the Czech Science Foundation (Grant No. P206/12/P065). M.H. acknowledges the support of the ERC CZ Project No. LL1302 sponsored by the Ministry of Education, Youth and Sports of the Czech Republic. M.K. acknowledges the support of research project MH CZ-DRO (UHHK, 00179906).

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Authors and Affiliations

  1. Department of Analytical Chemistry, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 53210, Pardubice, Czech Republic

    Robert Jirásko & Michal Holčapek

  2. Biomedical Research Centre, University Hospital Hradec Králové, Sokolská 581, 500 05, Hradec Králové, Czech Republic

    Martin Kuneš

  3. Research Group Mass Spectrometry and Proteomics, Max Planck Institute for Chemical Ecology, Hans-Knöll-Str. 8, 07745, Jena, Germany

    Aleš Svatoš

Authors
  1. Robert Jirásko
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  2. Michal Holčapek
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  3. Martin Kuneš
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  4. Aleš Svatoš
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Correspondence to Robert Jirásko.

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Jirásko, R., Holčapek, M., Kuneš, M. et al. Distribution study of atorvastatin and its metabolites in rat tissues using combined information from UHPLC/MS and MALDI-Orbitrap-MS imaging. Anal Bioanal Chem 406, 4601–4610 (2014). https://doi.org/10.1007/s00216-014-7880-y

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  • DOI: https://doi.org/10.1007/s00216-014-7880-y

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