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Research ArticleArticle

Coupling of Liquid Chromatography/Tandem Mass Spectrometry and Liquid Chromatography/Solid-Phase Extraction/NMR Techniques for the Structural Identification of Metabolites following In Vitro Biotransformation of SUR1-Selective ATP-Sensitive Potassium Channel Openers

Florian Gillotin, Patrice Chiap, Michel Frédérich, Jean-Claude Van Heugen, Pierre Francotte, Philippe Lebrun, Bernard Pirotte and Pascal de Tullio
Drug Metabolism and Disposition February 2010, 38 (2) 232-240; DOI: https://doi.org/10.1124/dmd.109.028928
Florian Gillotin
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Patrice Chiap
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Michel Frédérich
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Jean-Claude Van Heugen
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Pierre Francotte
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Philippe Lebrun
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Bernard Pirotte
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Pascal de Tullio
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Abstract

SUR1-selective ATP-sensitive potassium channel openers (PCOs) have been shown to be of clinical value for the treatment of several metabolic disorders, including type I and type II diabetes, obesity, and hyperinsulinemia. Taking into account these promising therapeutic benefits, different series of 3-alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides structurally related to diazoxide were developed. In view of the lead optimization process of the series, knowledge of absorption, distribution, metabolism, excretion, and toxicity parameters, and more particularly the metabolic fate of these compounds, is a fundamental requirement. For such a purpose, two selected promising compounds [7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide (BPDZ 73) and 7-chloro-3-(3-pentylamino)-4H-1,2,4-benzothiadiazine 1,1-dioxide (BPDZ 157)] were incubated in the presence of phenobarbital-induced rat liver microsomes to produce expected mammal in vivo phase I metabolites. The resulting major metabolites were then analyzed by both mass spectrometry (MS) and NMR to completely elucidate their chemical structures. The two compounds were also further incubated in the presence of nontreated rats and human microsomes to compare the metabolic profiles. In the present study, the combined use of an exact mass liquid chromatography (LC)/tandem MS platform and an LC/solid-phase extraction/NMR system allowed the clarification of some unresolved structural assessments in the accurate chemical structure elucidation process of the selected PCO drugs. These results greatly help the optimization of the lead compounds.

Footnotes

  • This work was supported by grants from the National Fund for Scientific Research (Belgium).

  • P.d.T. and M.F. are Senior Research Associates for the National Fund for Scientific Research (Belgium). P.L. is Research Director for the National Fund for Scientific Research (Belgium).

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.109.028928.

  • KATP channel
    ATP-sensitive potassium channel
    PCO
    potassium channel opener
    BPDZ 73
    7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide
    BPDZ 157
    7-chloro-3-(3-pentylamino)-4H-1,2,4-benzothiadiazine 1,1-dioxide
    PB
    phenobarbital
    P450
    cytochrome P450
    LC
    liquid chromatography
    SPE
    solid-phase extraction
    MS/MS
    tandem mass spectrometry
    ACN
    acetonitrile
    COSY
    correlation spectroscopy
    BPDZ 44
    3-(1′,2′-dimethylpropyl)amino-4H-pyrido[4,3-e][1,2,4]thiadiazine 1,1-dioxide
    BPDZ 154
    6,7-dichloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide
    BPDZ 414
    6,7-difluoro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide
    BPDZ 256
    6-chloro-3-cyclobutylamino-7-fluoro-4H-1,2,4-benzothiadiazine 1,1-dioxide.

    • Received June 10, 2009.
    • Accepted October 27, 2009.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (2)
Drug Metabolism and Disposition
Vol. 38, Issue 2
1 Feb 2010
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Research ArticleArticle

Coupling of Liquid Chromatography/Tandem Mass Spectrometry and Liquid Chromatography/Solid-Phase Extraction/NMR Techniques for the Structural Identification of Metabolites following In Vitro Biotransformation of SUR1-Selective ATP-Sensitive Potassium Channel Openers

Florian Gillotin, Patrice Chiap, Michel Frédérich, Jean-Claude Van Heugen, Pierre Francotte, Philippe Lebrun, Bernard Pirotte and Pascal de Tullio
Drug Metabolism and Disposition February 1, 2010, 38 (2) 232-240; DOI: https://doi.org/10.1124/dmd.109.028928

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Research ArticleArticle

Coupling of Liquid Chromatography/Tandem Mass Spectrometry and Liquid Chromatography/Solid-Phase Extraction/NMR Techniques for the Structural Identification of Metabolites following In Vitro Biotransformation of SUR1-Selective ATP-Sensitive Potassium Channel Openers

Florian Gillotin, Patrice Chiap, Michel Frédérich, Jean-Claude Van Heugen, Pierre Francotte, Philippe Lebrun, Bernard Pirotte and Pascal de Tullio
Drug Metabolism and Disposition February 1, 2010, 38 (2) 232-240; DOI: https://doi.org/10.1124/dmd.109.028928
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