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Research ArticleArticle

METABOLISM AND DISPOSITION OF IMATINIB MESYLATE IN HEALTHY VOLUNTEERS

Hans-Peter Gschwind, Ulrike Pfaar, Felix Waldmeier, Markus Zollinger, Claudia Sayer, Peter Zbinden, Michael Hayes, Rolf Pokorny, Michael Seiberling, Monique Ben-Am, Bin Peng and Gerhard Gross
Drug Metabolism and Disposition October 2005, 33 (10) 1503-1512; DOI: https://doi.org/10.1124/dmd.105.004283
Hans-Peter Gschwind
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Ulrike Pfaar
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Felix Waldmeier
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Markus Zollinger
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Claudia Sayer
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Peter Zbinden
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Michael Hayes
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Rolf Pokorny
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Michael Seiberling
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Monique Ben-Am
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Bin Peng
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Gerhard Gross
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Abstract

Imatinib mesylate (GLEEVEC, GLIVEC, formerly STI571) has demonstrated unprecedented efficacy as first-line therapy for treatment for all phases of chronic myelogenous leukemia and metastatic and unresectable malignant gastrointestinal stromal tumors. Disposition and biotransformation of imatinib were studied in four male healthy volunteers after a single oral dose of 239 mg of 14C-labeled imatinib mesylate. Biological fluids were analyzed for total radioactivity, imatinib, and its main metabolite CGP74588. Metabolite patterns were determined by radio-high-performance liquid chromatography with off-line microplate solid scintillation counting and characterized by liquid chromatography-mass spectrometry. Imatinib treatment was well tolerated without serious adverse events. Absorption was rapid (tmax 1-2 h) and complete with imatinib as the major radioactive compound in plasma. Maximum plasma concentrations were 0.921 ± 0.095 μg/ml (mean ± S.D., n = 4) for imatinib and 0.115 ± 0.026 μg/ml for the pharmacologically active N-desmethyl metabolite (CGP74588). Mean plasma terminal elimination half-lives were 13.5 ± 0.9 h for imatinib, 20.6 ± 1.7 h for CGP74588, and 57.3 ± 12.5 h for 14C radioactivity. Imatinib was predominantly cleared through oxidative metabolism. Approximately 65 and 9% of total systemic exposure [AUC0-24 h (area under the concentration time curve) of radioactivity] corresponded to imatinib and CGP74588, respectively. The remaining proportion corresponded mainly to oxidized derivatives of imatinib and CGP74588. Imatinib and its metabolites were excreted predominantly via the biliary-fecal route. Excretion of radioactivity was slow with a mean radiocarbon recovery of 80% within 7 days (67% in feces, 13% in urine). Approximately 28 and 13% of the dose in the excreta corresponded to imatinib and CGP74588, respectively.

Footnotes

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

  • doi:10.1124/dmd.105.004283.

  • ABBREVIATIONS: BCR-ABL, p210 BCR-ABL fusion protein found in patients with chronic myelogenous leukemia; CML, chronic myelogenous leukemia; AUC, area under the concentration time curve; GIST, gastrointestinal stromal tumor(s); HPLC, high performance liquid chromatography; LC-MS, liquid chromatography coupled to mass spectrometry; LSC, liquid scintillation counting; PDGFR, platelet-derived growth factor receptor; radio-HPLC, HPLC coupled to radioactivity detection; CGP74588, N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-4-piperazin-1-ylmethyl-benzamide; CGP72383, N-4-methyl-3-[4-(1-oxy-pyridin-3-yl)-pyrimidin-2-ylamino]-phenyl}-4-(4-methyl-piperazin-1-ylmethyl)-benzamide; CGP71422, 4-(4-methyl-4-oxy-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide; AFN911, N-[4-hydroxymethyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-4-(4-methyl-piperazin-1-ylmethyl)-benzamide; APG050, 4-(4-methyl-3-oxo-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide; APG049, N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-4-(3-oxo-piperazin-1-ylmethyl)-benzamide.

    • Received February 22, 2005.
    • Accepted July 6, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 33 (10)
Drug Metabolism and Disposition
Vol. 33, Issue 10
1 Oct 2005
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Research ArticleArticle

METABOLISM AND DISPOSITION OF IMATINIB MESYLATE IN HEALTHY VOLUNTEERS

Hans-Peter Gschwind, Ulrike Pfaar, Felix Waldmeier, Markus Zollinger, Claudia Sayer, Peter Zbinden, Michael Hayes, Rolf Pokorny, Michael Seiberling, Monique Ben-Am, Bin Peng and Gerhard Gross
Drug Metabolism and Disposition October 1, 2005, 33 (10) 1503-1512; DOI: https://doi.org/10.1124/dmd.105.004283

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Research ArticleArticle

METABOLISM AND DISPOSITION OF IMATINIB MESYLATE IN HEALTHY VOLUNTEERS

Hans-Peter Gschwind, Ulrike Pfaar, Felix Waldmeier, Markus Zollinger, Claudia Sayer, Peter Zbinden, Michael Hayes, Rolf Pokorny, Michael Seiberling, Monique Ben-Am, Bin Peng and Gerhard Gross
Drug Metabolism and Disposition October 1, 2005, 33 (10) 1503-1512; DOI: https://doi.org/10.1124/dmd.105.004283
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