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Research ArticleArticle

Metabolite Profiling of Bendamustine in Urine of Cancer Patients after Administration of [14C]Bendamustine

Anne-Charlotte Dubbelman, Robert S. Jansen, Hilde Rosing, Mona Darwish, Edward Hellriegel, Philmore Robertson Jr., Jan H. M. Schellens and Jos H. Beijnen
Drug Metabolism and Disposition July 2012, 40 (7) 1297-1307; DOI: https://doi.org/10.1124/dmd.112.045229
Anne-Charlotte Dubbelman
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Robert S. Jansen
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Hilde Rosing
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Mona Darwish
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Edward Hellriegel
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Philmore Robertson Jr.
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Jan H. M. Schellens
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Jos H. Beijnen
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This article has a correction. Please see:

  • Correction to “Metabolite Profiling of Bendamustine in Urine of Cancer Patients after Administration of [14C]Bendamustine” - December 01, 2015

Abstract

Bendamustine is an alkylating agent consisting of a mechlorethamine derivative, a benzimidazole group, and a butyric acid substituent. A human mass balance study showed that bendamustine is extensively metabolized and subsequently excreted in urine. However, limited information is available on the metabolite profile of bendamustine in human urine. The objective of this study was to elucidate the metabolic pathways of bendamustine in humans by identification of its metabolites excreted in urine. Human urine samples were collected up to 168 h after an intravenous infusion of 120 mg/m2 (80–95 μCi) [14C]bendamustine. Metabolites of [14C]bendamustine were identified using liquid chromatography (high-resolution)-tandem mass spectrometry with off-line radioactivity detection. Bendamustine and a total of 25 bendamustine-related compounds were detected. Observed metabolic conversions at the benzimidazole and butyric acid moiety were N-demethylation and γ-hydroxylation. In addition, various other combinations of these conversions with modifications at the mechlorethamine moiety were observed, including hydrolysis (the primary metabolic pathway), cysteine conjugation, and subsequent biotransformation to mercapturic acid and thiol derivatives, N-dealkylation, oxidation, and conjugation with phosphate, creatinine, and uric acid. Bendamustine-derived products containing phosphate, creatinine, and uric acid conjugates were also detected in control urine incubated with bendamustine. Metabolites that were excreted up to 168 h after the infusion included products of dihydrolysis and cysteine conjugation of bendamustine and γ-hydroxybendamustine. The range of metabolic reactions is generally consistent with those reported for rat urine and bile, suggesting that the overall processes involved in metabolic elimination are qualitatively the same in rats and humans.

Footnotes

  • This work was supported by Teva Pharmaceutical Industries Ltd. The primary laboratory of origin was The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands.

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

    http://dx.doi.org/10.1124/dmd.112.045229.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    HPLC
    high-performance liquid chromatography
    MS
    mass spectrometry
    LSC
    liquid scintillation counting
    LC
    liquid chromatography
    MS/MS
    liquid chromatography-tandem mass spectrometry.

  • Received February 27, 2012.
  • Accepted April 3, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (7)
Drug Metabolism and Disposition
Vol. 40, Issue 7
1 Jul 2012
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Research ArticleArticle

METABOLITE PROFILING OF BENDAMUSTINE IN HUMAN URINE

Anne-Charlotte Dubbelman, Robert S. Jansen, Hilde Rosing, Mona Darwish, Edward Hellriegel, Philmore Robertson, Jan H. M. Schellens and Jos H. Beijnen
Drug Metabolism and Disposition July 1, 2012, 40 (7) 1297-1307; DOI: https://doi.org/10.1124/dmd.112.045229

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Research ArticleArticle

METABOLITE PROFILING OF BENDAMUSTINE IN HUMAN URINE

Anne-Charlotte Dubbelman, Robert S. Jansen, Hilde Rosing, Mona Darwish, Edward Hellriegel, Philmore Robertson, Jan H. M. Schellens and Jos H. Beijnen
Drug Metabolism and Disposition July 1, 2012, 40 (7) 1297-1307; DOI: https://doi.org/10.1124/dmd.112.045229
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