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Research ArticleArticle

Pharmacokinetics, Distribution, and Metabolism of [14C]Sunitinib in Rats, Monkeys, and Humans

Bill Speed, Hai-Zhi Bu, William F. Pool, Geoffrey W. Peng, Ellen Y. Wu, Shem Patyna, Carlo Bello and Ping Kang
Drug Metabolism and Disposition March 2012, 40 (3) 539-555; DOI: https://doi.org/10.1124/dmd.111.042853
Bill Speed
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Hai-Zhi Bu
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William F. Pool
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Geoffrey W. Peng
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Ellen Y. Wu
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Shem Patyna
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Carlo Bello
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Ping Kang
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Abstract

Sunitinib is an oral multitargeted tyrosine kinase inhibitor approved for the treatment of advanced renal cell carcinoma, imatinib-refractory gastrointestinal stromal tumor, and advanced pancreatic neuroendocrine tumors. The current studies were conducted to characterize the pharmacokinetics, distribution, and metabolism of sunitinib after intravenous and/or oral administrations of [14C]sunitinib in rats (5 mg/kg i.v., 15 mg/kg p.o.), monkeys (6 mg/kg p.o.), and humans (50 mg p.o.). After oral administration, plasma concentration of sunitinib and total radioactivity peaked from 3 to 8 h. Plasma terminal elimination half-lives of sunitinib were 8 h in rats, 17 h in monkeys, and 51 h in humans. The majority of radioactivity was excreted to the feces with a smaller fraction of radioactivity excreted to urine in all three species. The bioavailability in female rats was close to 100%, suggesting complete absorption of sunitinib. Whole-body autoradioluminography suggested radioactivity was distributed throughout rat tissues, with the majority of radioactivity cleared within 72 h. Radioactivity was eliminated more slowly from pigmented tissues. Sunitinib was extensively metabolized in all species. Many metabolites were detected both in urine and fecal extracts. The main metabolic pathways were N-de-ethylation and hydroxylation of indolylidene/dimethylpyrrole. N-Oxidation/hydroxylation/desaturation/deamination of N,N′-diethylamine and oxidative defluorination were the minor metabolic pathways. Des-ethyl metabolite M1 was the major circulating metabolite in all three species.

Footnotes

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

    http://dx.doi.org/10.1124/dmd.111.042853.

  • ABBREVIATIONS:

    HPLC
    high-performance liquid chromatography
    LC-MS/MS
    liquid chromatography/tandem mass spectrometry
    AUC
    area under the concentration
    IS
    internal standard
    ESI
    electrospray ionization
    P450
    cytochrome P450
    SU012487
    N,N-diethyl-2-[[5-[(Z)-(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carbonyl]amino]ethanamine oxide
    SU012662
    N-[2-(ethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide
    SU014335
    N-(2-aminoethyl)-5-[(Z)-(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide
    PHA-782584
    N-(2-diethylaminoethyl)-5-[(Z)-(5-hydroxy-2-oxo-indolin-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide
    PHA-77473
    N-(2-diethylaminoethyl)-5-[(5-fluoro-2-oxo-indolin-3-yl)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide.

  • Received September 16, 2011.
  • Accepted December 16, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (3)
Drug Metabolism and Disposition
Vol. 40, Issue 3
1 Mar 2012
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Research ArticleArticle

[14C]SUNITINIB IN RATS, MONKEYS, AND HUMANS

Bill Speed, Hai-Zhi Bu, William F. Pool, Geoffrey W. Peng, Ellen Y. Wu, Shem Patyna, Carlo Bello and Ping Kang
Drug Metabolism and Disposition March 1, 2012, 40 (3) 539-555; DOI: https://doi.org/10.1124/dmd.111.042853

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Research ArticleArticle

[14C]SUNITINIB IN RATS, MONKEYS, AND HUMANS

Bill Speed, Hai-Zhi Bu, William F. Pool, Geoffrey W. Peng, Ellen Y. Wu, Shem Patyna, Carlo Bello and Ping Kang
Drug Metabolism and Disposition March 1, 2012, 40 (3) 539-555; DOI: https://doi.org/10.1124/dmd.111.042853
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