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Research ArticleArticle

Characterization of the In Vitro and In Vivo Metabolism and Disposition and Cytochrome P450 Inhibition/Induction Profile of Saxagliptin in Human

Hong Su, David W. Boulton, Anthony Barros Jr., Lifei Wang, Kai Cao, Samuel J. Bonacorsi Jr., Ramaswamy A. Iyer, W. Griffith Humphreys and Lisa J. Christopher
Drug Metabolism and Disposition July 2012, 40 (7) 1345-1356; DOI: https://doi.org/10.1124/dmd.112.045450
Hong Su
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David W. Boulton
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Anthony Barros Jr.
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Lifei Wang
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Kai Cao
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Samuel J. Bonacorsi Jr.
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Ramaswamy A. Iyer
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W. Griffith Humphreys
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Lisa J. Christopher
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Abstract

Saxagliptin is a potent dipeptidyl peptidase-4 inhibitor approved for the treatment of type 2 diabetes mellitus. The pharmacokinetics and disposition of [14C]saxagliptin were investigated in healthy male subjects after a single 50-mg (91.5 μCi) oral dose. Saxagliptin was rapidly absorbed (Tmax, 0.5 h). Unchanged saxagliptin and 5-hydroxy saxagliptin (M2), a major, active metabolite, were the prominent drug-related components in the plasma, together accounting for most of the circulating radioactivity. Approximately 97% of the administered radioactivity was recovered in the excreta within 7 days postdose, of which 74.9% was eliminated in the urine and 22.1% was excreted in the feces. The parent compound and M2 represented 24.0 and 44.1%, respectively, of the radioactivity recovered in the urine and feces combined. Taken together, the excretion data suggest that saxagliptin was well absorbed and was subsequently cleared by both urinary excretion and metabolism; the formation of M2 was the major metabolic pathway. Additional minor metabolic pathways included hydroxylation at other positions and glucuronide or sulfate conjugation. Cytochrome P450 (P450) enzymes CYP3A4 and CYP3A5 metabolized saxagliptin and formed M2. Kinetic experiments indicated that the catalytic efficiency (Vmax/Km) for CYP3A4 was approximately 4-fold higher than that for CYP3A5. Therefore, it is unlikely that variability in expression levels of CYP3A5 due to genetic polymorphism will impact clearance of saxagliptin. Saxagliptin and M2 each showed little potential to inhibit or induce important P450 enzymes, suggesting that saxagliptin is unlikely to affect the metabolic clearance of coadministered drugs that are substrates for these enzymes.

Footnotes

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

    http://dx.doi.org/10.1124/dmd.112.045450.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    DPP4
    dipeptidyl peptidase-4
    GLP-1
    glucagon-like peptide-1
    P450
    cytochrome P450
    HPLC
    high-performance liquid chromatography
    HLM
    human liver microsomes
    LSC
    liquid scintillation counting
    LC-MS/MS
    liquid chromatography with tandem mass spectrometry
    MRM
    multiple reaction monitoring
    AUC
    area under plasma concentration-time curve
    T-HALF
    terminal phase half-life
    CLR
    renal clearance
    DMSO
    dimethyl sulfoxide
    3-MC
    3-methylcholanthrene
    PB
    phenobarbital
    RIF
    rifampicin
    CT
    threshold cycle.

  • Received March 2, 2012.
  • Accepted April 10, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (7)
Drug Metabolism and Disposition
Vol. 40, Issue 7
1 Jul 2012
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Research ArticleArticle

METABOLISM AND DISPOSITION OF SAXAGLIPTIN IN HUMANS

Hong Su, David W. Boulton, Anthony Barros, Lifei Wang, Kai Cao, Samuel J. Bonacorsi, Ramaswamy A. Iyer, W. Griffith Humphreys and Lisa J. Christopher
Drug Metabolism and Disposition July 1, 2012, 40 (7) 1345-1356; DOI: https://doi.org/10.1124/dmd.112.045450

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Research ArticleArticle

METABOLISM AND DISPOSITION OF SAXAGLIPTIN IN HUMANS

Hong Su, David W. Boulton, Anthony Barros, Lifei Wang, Kai Cao, Samuel J. Bonacorsi, Ramaswamy A. Iyer, W. Griffith Humphreys and Lisa J. Christopher
Drug Metabolism and Disposition July 1, 2012, 40 (7) 1345-1356; DOI: https://doi.org/10.1124/dmd.112.045450
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