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Research ArticleArticle

Species-Specific Metabolism of SGX523 by Aldehyde Oxidase and the Toxicological Implications

Sharon Diamond, Jason Boer, Thomas P. Maduskuie Jr., Nikoo Falahatpisheh, Yu Li and Swamy Yeleswaram
Drug Metabolism and Disposition August 2010, 38 (8) 1277-1285; DOI: https://doi.org/10.1124/dmd.110.032375
Sharon Diamond
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Jason Boer
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Thomas P. Maduskuie Jr.
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Nikoo Falahatpisheh
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Yu Li
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Swamy Yeleswaram
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Abstract

An investigation was conducted to follow up on the apparent species-dependent toxicity reported for 6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylthio)quinoline (SGX523), a mesenchymal-epithelial transition factor (c-MET) inhibitor that entered clinical development for the treatment of solid tumors. Patients treated with SGX523 exhibited compromised renal function presumably resulting from crystal deposits in renal tubules. Our independent metabo‘lite profiling of SGX523 indicates that a major NADPH-independent, late-eluting metabolite [6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylthio)quinolin-2(1H)-one (M11)] was generated by monkey and human liver S-9, and to a lesser extent by rat S-9, whereas M11 was absent in dog S-9 incubations. We confirmed the identity of M11 as 2-quinolinone-SGX523. Experiments with various molybdenum hydroxylase inhibitors showed that aldehyde oxidase (AO), and not xanthine oxidase, metabolized SGX523 to M11 in monkey and human liver cytosol. In addition, the oxygen incorporated into M11 was derived from water rather than atmospheric oxygen, corroborating M11 formation via AO. After oral dosing in monkeys, metabolite profiling of plasma and urine showed that SGX523 was indeed metabolized to M11 and its N-demethyl analog (M8). In urine, M11 levels were ∼70-fold greater than that of SGX523, and the solubility of M11 in urine was only 3% of that of SGX523. In summary, SGX523 is metabolized by AO in a species-specific manner to a markedly less-soluble metabolite, M11. We propose that M11 is likely involved in the observed obstructive nephropathy reported in clinical studies. Moreover, this study illustrates the need to conduct thorough metabolic evaluations early in drug development to select the most relevant nonclinical species for toxicological evaluation.

Footnotes

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

    doi:10.1124/dmd.110.032375.

  • ABBREVIATIONS:

    c-MET
    mesenchymal-epithelial transition factor
    SGX523
    (6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylthio)quinoline
    SKF525-A
    proadifen hydrochloride
    DMSO
    dimethyl sulfoxide
    M11/2-quinolinone-SGX523
    6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylthio)quinolin-2(1H)-one
    XO
    xanthine oxidase
    AO
    aldehyde oxidase
    LC/(MS)/MS
    liquid chromatography/(tandem) mass spectrometry
    MRM
    multiple reaction monitoring
    P450
    cytochrome P450
    SB-277011
    trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl) ethyl]cyclohexyl]-4-quinolinecarboxamide.

  • Received January 25, 2010.
  • Accepted April 23, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (8)
Drug Metabolism and Disposition
Vol. 38, Issue 8
1 Aug 2010
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Research ArticleArticle

Species-Specific Metabolism of SGX523 by Aldehyde Oxidase and the Toxicological Implications

Sharon Diamond, Jason Boer, Thomas P. Maduskuie, Nikoo Falahatpisheh, Yu Li and Swamy Yeleswaram
Drug Metabolism and Disposition August 1, 2010, 38 (8) 1277-1285; DOI: https://doi.org/10.1124/dmd.110.032375

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Research ArticleArticle

Species-Specific Metabolism of SGX523 by Aldehyde Oxidase and the Toxicological Implications

Sharon Diamond, Jason Boer, Thomas P. Maduskuie, Nikoo Falahatpisheh, Yu Li and Swamy Yeleswaram
Drug Metabolism and Disposition August 1, 2010, 38 (8) 1277-1285; DOI: https://doi.org/10.1124/dmd.110.032375
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