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Research ArticleArticle

Metabolism and Disposition of the Antihypertensive Agent Moxonidine in Humans

Minxia M. He, Trent L. Abraham, Thomas J. Lindsay, Hans C. Schaefer, Isabelle J. Pouliquen, Chris Payne, Boris Czeskis, Lisa A. Shipley, Stuart D. Oliver and Malcolm I. Mitchell
Drug Metabolism and Disposition March 2003, 31 (3) 334-342; DOI: https://doi.org/10.1124/dmd.31.3.334
Minxia M. He
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Trent L. Abraham
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Thomas J. Lindsay
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Hans C. Schaefer
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Isabelle J. Pouliquen
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Chris Payne
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Boris Czeskis
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Lisa A. Shipley
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Stuart D. Oliver
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Malcolm I. Mitchell
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Abstract

The metabolism and pharmacokinetics of moxonidine, a potent central-acting antihypertensive agent, were studied in four healthy subjects after a single oral administration of approximately 1 mg (∼60 μCi) of [14C3]moxonidine. Moxonidine was rapidly absorbed, with peak plasma concentration achieved between 0.5 to 2 h postdose. The maximal plasma concentration and the area under the curve of unchanged moxonidine are lower than those determined for radioactivity, indicating presence of circulating metabolite(s). The total recovery of radiocarbon over 120 h ranged from 99.6 to 105.2%, with 92.3 to 103.3% of the radioactivity excreted in the urine and only 1.9 to 7.3% of the dose excreted in the feces. Thus, renal elimination represented the principal route of excretion of radioactivity. Metabolites of moxonidine were identified in urine and plasma samples by high performance liquid chromatography and liquid chromatography-tandem mass spectrometry. Oxidation of moxonidine on the methyl group or on the imidazoline ring resulted in the formation of hydroxymethyl moxonidine, hydroxy moxonidine, dihydroxy moxonidine, and dehydrogenated moxonidine. Metabolite profiling results indicated that parent moxonidine was the most abundant component in the urine. The dehydrogenated moxonidine was the major urinary metabolite as well as the major circulating metabolite. Moxonidine also underwent phase II metabolism, generating a cysteine conjugate. In summary, moxonidine is well absorbed after oral administration. The major clearance pathway for moxonidine in humans is via renal elimination. Furthermore, seven metabolites were identified with three metabolites unique to humans.

Footnotes

  • 1 Current address: Boehringer Ingelheim Pharma KG, Clinical Pharmacokinetics, Birkendorfer Strasse 65, 88397 Biberach, Germany.

  • Abbreviations used are::
    HPLC
    high performance liquid chromatography
    LC/MS/MS
    liquid chromatography-tandem mass spectrometry
    MS
    mass spectrometry
    APCI
    atmospheric pressure chemical ionization
    RE
    relative error, a measure of accuracy of a group of values
    RSD
    relative standard deviation, a measure of precision
    AUC
    area under the plasma concentration versus time curve
    OCT
    organic cation transporter
    M1
    dehydrogenated moxonidine
    M2
    putative N-oxide of dehydrogenated moxonidine
    M3
    hydroxy moxonidine
    M4
    dihydroxy moxonidine
    M5
    hydroxymethyl moxonidine
    M6
    cysteine conjugate minus chlorine
    M7
    unknown metabolite
    GSH
    glutathione
    TLC
    thin layer chromatography
    • Received October 1, 2002.
    • Accepted December 2, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 31 (3)
Drug Metabolism and Disposition
Vol. 31, Issue 3
1 Mar 2003
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Research ArticleArticle

Metabolism and Disposition of the Antihypertensive Agent Moxonidine in Humans

Minxia M. He, Trent L. Abraham, Thomas J. Lindsay, Hans C. Schaefer, Isabelle J. Pouliquen, Chris Payne, Boris Czeskis, Lisa A. Shipley, Stuart D. Oliver and Malcolm I. Mitchell
Drug Metabolism and Disposition March 1, 2003, 31 (3) 334-342; DOI: https://doi.org/10.1124/dmd.31.3.334

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Research ArticleArticle

Metabolism and Disposition of the Antihypertensive Agent Moxonidine in Humans

Minxia M. He, Trent L. Abraham, Thomas J. Lindsay, Hans C. Schaefer, Isabelle J. Pouliquen, Chris Payne, Boris Czeskis, Lisa A. Shipley, Stuart D. Oliver and Malcolm I. Mitchell
Drug Metabolism and Disposition March 1, 2003, 31 (3) 334-342; DOI: https://doi.org/10.1124/dmd.31.3.334
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