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Research ArticleArticle

Identification of Novel Metabolites of Colchicine in Rat Bile Facilitated by Enhanced Online Radiometric Detection

Lin Xu, Bruce Adams, Valentina V. Jeliazkova-Mecheva, Laird Trimble, Gloria Kwei and Andreas Harsch
Drug Metabolism and Disposition April 2008, 36 (4) 731-739; DOI: https://doi.org/10.1124/dmd.107.019463
Lin Xu
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Bruce Adams
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Valentina V. Jeliazkova-Mecheva
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Laird Trimble
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Gloria Kwei
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Andreas Harsch
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Abstract

Three novel conjugation metabolites of colchicine were identified in rat bile facilitated by enhanced on-line liquid chromatography-accurate radioisotope counting. The known 2- and 3-demethylcolchicines (DMCs) underwent O-sulfate conjugation in addition to the previously described O-glucuronidation. 2-DMC was preferably O-glucuronidated, whereas 3-DMC predominantly yielded O-sulfation conjugates, indicating phase II conjugation regiopreferences. Moreover, M1 was identified as a novel glutathione conjugate and a possible biotransformation pathway for its formation was proposed. The known 2-DMC (M6), 3-DMC (M7), 2-DMC glucuronide (M4), and novel 3-DMC sulfate (M3) were confirmed as the major metabolites. Radiometric data were acquired by the XFlow liquid chromatography-accurate radioisotope counting (XFlow LC-ARC) system, a novel technology for dynamic control of both on-column and postcolumn high-performance liquid chromatography flow rates to maximize sensitivity and resolution of radiochromatograms. A comparative evaluation was also performed between the XFlow LC-ARC system and a conventional flow radiometric detection system using bile samples from an in vivo disposition study of colchicine in male Sprague-Dawley rats. Results demonstrated a 20-fold sensitivity improvement of the XFlow LC-ARC system in comparison with radioactivity detection by conventional flow scintillation analyzers. The dynamic flow mode also provided the best chromatographic resolution. Unambiguous metabolite identification was performed by high-resolution mass spectrometry and nuclear magnetic resonance analysis.

  • Received October 26, 2007.
  • Accepted January 23, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (4)
Drug Metabolism and Disposition
Vol. 36, Issue 4
1 Apr 2008
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Research ArticleArticle

Identification of Novel Metabolites of Colchicine in Rat Bile Facilitated by Enhanced Online Radiometric Detection

Lin Xu, Bruce Adams, Valentina V. Jeliazkova-Mecheva, Laird Trimble, Gloria Kwei and Andreas Harsch
Drug Metabolism and Disposition April 1, 2008, 36 (4) 731-739; DOI: https://doi.org/10.1124/dmd.107.019463

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Research ArticleArticle

Identification of Novel Metabolites of Colchicine in Rat Bile Facilitated by Enhanced Online Radiometric Detection

Lin Xu, Bruce Adams, Valentina V. Jeliazkova-Mecheva, Laird Trimble, Gloria Kwei and Andreas Harsch
Drug Metabolism and Disposition April 1, 2008, 36 (4) 731-739; DOI: https://doi.org/10.1124/dmd.107.019463
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