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Research ArticleArticle

Extensive Metabolism and Hepatic Accumulation of Gemcitabine After Multiple Oral and Intravenous Administration in Mice

Stephan A. Veltkamp, Dick Pluim, Olaf van Tellingen, Jos H. Beijnen and Jan H. M. Schellens
Drug Metabolism and Disposition August 2008, 36 (8) 1606-1615; DOI: https://doi.org/10.1124/dmd.108.021048
Stephan A. Veltkamp
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Dick Pluim
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Olaf van Tellingen
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Jos H. Beijnen
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Jan H. M. Schellens
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Abstract

In a clinical study with oral gemcitabine (2′,2′-difluorodeoxycytidine, dFdC), we found that gemcitabine was hepatotoxic and extensively metabolized to 2′,2′-difluorodeoxyuridine (dFdU) after continuous oral dosing. The main metabolite dFdU had a long terminal half-life after oral administration. Our hypothesis was that dFdU and/or phosphorylated metabolites of gemcitabine accumulated in the liver after multiple oral dosing. In this study, mice were treated with oral or i.v. dFdC at a single dose (1qd×1d) or at multiple doses once daily for 7 days (1qd×7d) or seven times daily (7qd×1d). Blood, liver, kidneys, and lungs were collected at several time points. Urine samples were collected after i.v. dFdC, and peripheral blood mononuclear cells were collected 7qd×1d dosing of dFdC. The nucleosides dFdC and dFdU as well as the nucleotides gemcitabine monophosphate (dFdC-MP), diphosphate, and triphosphate (dFdC-TP) and dFdU monophosphate, diphosphate (dFdU-DP), and triphosphate (dFdU-TP) were simultaneously quantified by high-performance liquid chromatography with ultraviolet and radioisotope detection. We demonstrate that phosphorylated metabolites of both dFdC and dFdU are formed in mice, primarily consisting of dFdC-MP, dFdC-TP, and dFdU-TP. Multiple dosing of dFdC leads to substantial hepatic and renal accumulation of dFdC-TP and dFdU-TP, which have a more pronounced liver accumulation after oral than after i.v. dosing. The presence of dFdC-MP, dFdC-TP, and dFdU-TP in plasma and urine suggests efflux of these potentially toxic metabolites. Our results show that dFdU, dFdC-TP, and dFdU-TP accumulate in the liver after multiple dosing of dFdC in mice and might be associated with hepatotoxicity of oral dFdC in patients.

Footnotes

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

  • doi:10.1124/dmd.108.021048.

  • ABBREVIATIONS: dFdC, 2′,2′-difluorodeoxycytidine (gemcitabine); dCK, deoxycytidine kinase; dFdC-MP, gemcitabine monophosphate; dFdC-TP, gemcitabine triphosphate; dFdC-DP, gemcitabine diphosphate; dFdU, 2′,2′-difluorodeoxyuridine; CDA, cytidine deaminase; dFdU-TP, dFdU triphosphate; PBMC, peripheral blood mononuclear cell; hCNT1, human concentrative nucleoside transporter type 1; PK, pharmacokinetics; 1qd×1d, single dose on day 1; 1qd×7d, once daily dosing for 7 days; 7qd×1d, seven times daily dosing for 1 day; dFdU-MP, dFdU monophosphate; dFdU-DP, dFdU diphosphate; THU, tetrahydrouridine; AP, alkaline phosphatase; HPLC, high-performance liquid chromatography; AUC, area under the curve.

    • Received February 14, 2008.
    • Accepted May 15, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (8)
Drug Metabolism and Disposition
Vol. 36, Issue 8
1 Aug 2008
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Research ArticleArticle

Extensive Metabolism and Hepatic Accumulation of Gemcitabine After Multiple Oral and Intravenous Administration in Mice

Stephan A. Veltkamp, Dick Pluim, Olaf van Tellingen, Jos H. Beijnen and Jan H. M. Schellens
Drug Metabolism and Disposition August 1, 2008, 36 (8) 1606-1615; DOI: https://doi.org/10.1124/dmd.108.021048

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Research ArticleArticle

Extensive Metabolism and Hepatic Accumulation of Gemcitabine After Multiple Oral and Intravenous Administration in Mice

Stephan A. Veltkamp, Dick Pluim, Olaf van Tellingen, Jos H. Beijnen and Jan H. M. Schellens
Drug Metabolism and Disposition August 1, 2008, 36 (8) 1606-1615; DOI: https://doi.org/10.1124/dmd.108.021048
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