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Research ArticleArticle

Deuterium Isotope Effects on Drug Pharmacokinetics. I. System-Dependent Effects of Specific Deuteration with Aldehyde Oxidase Cleared Drugs

Raman Sharma, Timothy J. Strelevitz, Hongying Gao, Alan J. Clark, Klaas Schildknegt, R. Scott Obach, Sharon L. Ripp, Douglas K. Spracklin, Larry M. Tremaine and Alfin D. N. Vaz
Drug Metabolism and Disposition March 2012, 40 (3) 625-634; DOI: https://doi.org/10.1124/dmd.111.042770
Raman Sharma
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Timothy J. Strelevitz
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Hongying Gao
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Alan J. Clark
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Klaas Schildknegt
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R. Scott Obach
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Sharon L. Ripp
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Douglas K. Spracklin
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Larry M. Tremaine
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Alfin D. N. Vaz
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Abstract

The pharmacokinetic properties of drugs may be altered by kinetic deuterium isotope effects. With specifically deuterated model substrates and drugs metabolized by aldehyde oxidase, we demonstrate how knowledge of the enzyme's reaction mechanism, species differences in the role played by other enzymes in a drug's metabolic clearance, and differences in systemic clearance mechanisms are critically important for the pharmacokinetic application of deuterium isotope effects. Ex vivo methods to project the in vivo outcome using deuterated carbazeran and zoniporide with hepatic systems demonstrate the importance of establishing the extent to which other metabolic enzymes contribute to the metabolic clearance mechanism. Differences in pharmacokinetic outcomes in guinea pig and rat, with the same metabolic clearance mechanism, show how species differences in the systemic clearance mechanism can affect the in vivo outcome. Overall, to gain from the application of deuteration as a strategy to alter drug pharmacokinetics, these studies demonstrate the importance of understanding the systemic clearance mechanism and knowing the identity of the metabolic enzymes involved, the extent to which they contribute to metabolic clearance, and the extent to which metabolism contributes to the systemic clearance.

Footnotes

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

    http://dx.doi.org/10.1124/dmd.111.042770.

  • ABBREVIATIONS:

    KDIE
    kinetic deuterium isotope effect
    LC
    liquid chromatography
    MS
    mass spectrometry
    QC
    quality control
    MRM
    multiple reaction monitoring
    AO
    aldehyde oxidase
    AUC
    area under the curve.

  • Received September 14, 2011.
  • Accepted December 15, 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

DEUTERIUM ISOTOPE EFFECTS ON DRUG PHARMACOKINETICS

Raman Sharma, Timothy J. Strelevitz, Hongying Gao, Alan J. Clark, Klaas Schildknegt, R. Scott Obach, Sharon L. Ripp, Douglas K. Spracklin, Larry M. Tremaine and Alfin D. N. Vaz
Drug Metabolism and Disposition March 1, 2012, 40 (3) 625-634; DOI: https://doi.org/10.1124/dmd.111.042770

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Research ArticleArticle

DEUTERIUM ISOTOPE EFFECTS ON DRUG PHARMACOKINETICS

Raman Sharma, Timothy J. Strelevitz, Hongying Gao, Alan J. Clark, Klaas Schildknegt, R. Scott Obach, Sharon L. Ripp, Douglas K. Spracklin, Larry M. Tremaine and Alfin D. N. Vaz
Drug Metabolism and Disposition March 1, 2012, 40 (3) 625-634; DOI: https://doi.org/10.1124/dmd.111.042770
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