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Research ArticleArticle

Cross-Species Comparison of the Metabolism and Excretion of Zoniporide: Contribution of Aldehyde Oxidase to Interspecies Differences

Deepak Dalvie, Chenghong Zhang, Weichao Chen, Teresa Smolarek, R. Scott Obach and Cho-Ming Loi
Drug Metabolism and Disposition April 2010, 38 (4) 641-654; DOI: https://doi.org/10.1124/dmd.109.030783
Deepak Dalvie
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Chenghong Zhang
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Weichao Chen
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Teresa Smolarek
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R. Scott Obach
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Cho-Ming Loi
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Abstract

Excretion and metabolism of zoniporide were investigated in humans after intravenous infusion of [14C]zoniporide at an 80-mg dose. Bile was the primary route of excretion because 57% of dose was recovered in the feces after intravenous infusion. Zoniporide was primarily cleared via metabolism in humans. 2-Oxozoniporide (M1) was the major excretory and circulating metabolite in humans and was catalyzed by aldehyde oxidase (Km of 3.4 μM and Vmax of 74 pmol/min/mg protein). Metabolites M2 (17% of the dose) and M3 (6.4% of circulating radioactivity), in which the guanidine moiety was hydrolyzed to a carboxylic acid, were also detected in human feces and plasma, respectively, suggesting that hydrolysis was another route of metabolism of zoniporide in humans. The metabolism and excretion of [14C]zoniporide in rats and dogs were also evaluated. As in humans, bile was the primary route of excretion of the radiolabeled material in both species, and metabolism was the primary route of clearance. A comparison of plasma metabolites showed that for M3, rats had a higher concentration than human or dog. M1 was absent in dog and present in human and rat plasma at comparable levels, whereas comparison of excreta showed that the total body burden of M1 was greater in rat than that in human. No further evaluation of M2 was considered because it was detected only in the human fecal extracts. Hence, no further toxicological evaluation of the three human metabolites was undertaken.

Footnotes

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

    doi:10.1124/dmd.109.030783.

  • ABBREVIATIONS:

    NHE-1
    sodium/hydrogen exchanger
    CL
    total clearance
    AUC
    area under plasma concentration versus time curve
    SBE
    sulfobutylether
    HPLC
    high-performance liquid chromatography
    MS
    mass spectrometry
    RAM
    radioactivity monitoring detector
    LC-ARC
    liquid chromatography-accurate radioisotope counting system
    CID
    collision-induced dissociation
    amu
    atomic mass units
    P450
    cytochrome P450.

    • Received October 13, 2009.
    • Accepted December 29, 2009.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (4)
Drug Metabolism and Disposition
Vol. 38, Issue 4
1 Apr 2010
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Research ArticleArticle

Cross-Species Comparison of the Metabolism and Excretion of Zoniporide: Contribution of Aldehyde Oxidase to Interspecies Differences

Deepak Dalvie, Chenghong Zhang, Weichao Chen, Teresa Smolarek, R. Scott Obach and Cho-Ming Loi
Drug Metabolism and Disposition April 1, 2010, 38 (4) 641-654; DOI: https://doi.org/10.1124/dmd.109.030783

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Research ArticleArticle

Cross-Species Comparison of the Metabolism and Excretion of Zoniporide: Contribution of Aldehyde Oxidase to Interspecies Differences

Deepak Dalvie, Chenghong Zhang, Weichao Chen, Teresa Smolarek, R. Scott Obach and Cho-Ming Loi
Drug Metabolism and Disposition April 1, 2010, 38 (4) 641-654; DOI: https://doi.org/10.1124/dmd.109.030783
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