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Research ArticleArticle

Metabolism and Disposition of Moxonidine in Fischer 344 Rats

Minxia M. He, Trent L. Abraham, Thomas J. Lindsay, Sylvia H. Chay, Boris A. Czeskis and Lisa A. Shipley
Drug Metabolism and Disposition April 2000, 28 (4) 446-459;
Minxia M. He
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Trent L. Abraham
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Thomas J. Lindsay
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Sylvia H. Chay
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Boris A. Czeskis
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Lisa A. Shipley
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Abstract

The metabolism and disposition of moxonidine (4-chloro-5-(imidazolidin-2-ylidenimino)-6-methoxy-2-methylpyrimidine), a potent central-acting antihypertensive agent, were investigated in F344 rats. After an i.v. or oral administration of 0.3 mg/kg of [14C]moxonidine, the maximum plasma concentrations of moxonidine were determined to be 146.0 and 4.0 ng/ml, respectively, and the elimination half-lives were 0.9 and 1.1 h, respectively. The oral bioavailability of moxonidine was determined to be 5.1%. The metabolic and elimination profiles of moxonidine were determined after an oral administration of 5 mg/kg of [14C]moxonidine. More than fifteen phase I and phase II metabolites of moxonidine were identified in the different biological matrices (urine, plasma, and bile). Oxidative metabolism of moxonidine leads to the formation of hydroxymethyl moxonidine and a carboxylic acid metabolite as the major metabolites. Several GSH conjugates, cysteinylglycine conjugates, cysteine conjugates, and a glucuronide conjugate were also identified in rat bile samples. The radiocarbon was eliminated primarily by urinary excretion in rats, with 59.5% of total radioactivity recovered in the urine and 38.4% recovered in the feces within 120 h. In bile duct-cannulated rats, about 39.7% of the radiolabeled dose was excreted in the urine, 32.6% excreted in the bile, and approximately 2% remained in the feces. The results from a quantitative whole body autoradiography study indicate that radiocarbon associated with [14C]moxonidine and/or its metabolites was widely distributed to tissues, with the highest levels of radioactivity observed in the kidney and liver. In summary, moxonidine is well absorbed, extensively metabolized, widely distributed into tissues, and rapidly eliminated in rats after oral administration.

Footnotes

  • Send reprint requests to: Dr. Minxia M. He, Department of Drug Metabolism and Disposition, DC 0710, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285. E-mail: He_Michelle_Minxia{at}Lilly.Com

  • Abbreviations used are::
    LC/MS
    liquid chromatography-mass spectrometry
    QWBA
    quantitative whole body autoradiography
    LC/MS/MS
    tandem mass spectrometry
    GST
    glutathioneS-transferase
    GC/MS
    gas chromatography/mass spectrometry
    Cmax
    peak plasma concentration
    Tmax
    time to reachCmax
    AUC
    area under the plasma concentration time curve
    BQL
    below the quantitation limit
    TCA
    trichloroacetic acid
    • Received August 20, 1999.
    • Accepted December 17, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 28 (4)
Drug Metabolism and Disposition
Vol. 28, Issue 4
1 Apr 2000
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Research ArticleArticle

Metabolism and Disposition of Moxonidine in Fischer 344 Rats

Minxia M. He, Trent L. Abraham, Thomas J. Lindsay, Sylvia H. Chay, Boris A. Czeskis and Lisa A. Shipley
Drug Metabolism and Disposition April 1, 2000, 28 (4) 446-459;

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Research ArticleArticle

Metabolism and Disposition of Moxonidine in Fischer 344 Rats

Minxia M. He, Trent L. Abraham, Thomas J. Lindsay, Sylvia H. Chay, Boris A. Czeskis and Lisa A. Shipley
Drug Metabolism and Disposition April 1, 2000, 28 (4) 446-459;
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