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Research ArticleArticle

Influence of MK-467, a Peripherally Acting α2-Adrenoceptor Antagonist on the Disposition of Intravenous Dexmedetomidine in Dogs

Juhana Honkavaara, Flavia Restitutti, Marja Raekallio, Kati Salla, Erja Kuusela, Ville Ranta-Panula, Valtteri Rinne, Outi Vainio and Mika Scheinin
Drug Metabolism and Disposition March 2012, 40 (3) 445-449; DOI: https://doi.org/10.1124/dmd.111.042671
Juhana Honkavaara
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Flavia Restitutti
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Marja Raekallio
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Kati Salla
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Erja Kuusela
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Ville Ranta-Panula
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Valtteri Rinne
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Outi Vainio
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Mika Scheinin
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Abstract

Growing evidence supports the use of (2R-trans)-N-(2-(1,3,4,7,12b-hexahydro-2′-oxo-spiro(2H-benzofuro(2,3-a)quinolizine-2,4′-imidazolidin)-3′-yl)ethyl) methanesulfonamide (MK-467), a peripherally acting α2-adrenoceptor antagonist, in conjunction with the sedative-anesthetic agent dexmedetomidine in animals to avoid hemodynamic compromise. We evaluated the possible effects of different doses of MK-467 on the plasma concentrations of dexmedetomidine in eight beagle dogs. Both drugs were administered intravenously. Each dog received five treatments: dexmedetomidine alone (10 μg/kg), MK-467 alone (250 μg/kg), and dexmedetomidine (10 μg/kg) combined with different doses of MK-467 (250, 500, and 750 μg/kg) in a randomized, crossover fashion. Selected pharmacokinetic parameters were calculated. The area under the time-concentration curve of dexmedetomidine was significantly greater after dexmedetomidine alone (by 101 ± 20%, mean ± 95% confidence interval) compared with that after dexmedetomidine and 250 μg/kg MK-467. Increasing the dose of the antagonist had no further effect on the exposure to dexmedetomidine. The apparent volume of distribution of dexmedetomidine was significantly smaller after dexmedetomidine alone compared with that after all treatments that included MK-467. Dexmedetomidine (10 μg/kg) did not significantly influence the plasma concentrations of MK-467 (250 μg/kg). The results suggest that the peripherally acting α2-adrenoceptor antagonist MK-467 markedly influenced the early disposition of dexmedetomidine without obvious effects on the later plasma concentrations of the drug.

Footnotes

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

    http://dx.doi.org/10.1124/dmd.111.042671.

  • ABBREVIATIONS:

    MK-467
    (2R-trans)-N-(2-(1,3,4,7,12b-hexahydro-2′-oxo-spiro(2H-benzofuro(2,3-a)quinolizine-2,4′-imidazolidin)-3′-yl)ethyl) methanesulfonamide
    AUC
    area under the time-concentration curve.

  • Received September 6, 2011.
  • Accepted November 23, 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

ALTERED DISPOSITION OF DEXMEDETOMIDINE BY MK-467 IN DOGS

Juhana Honkavaara, Flavia Restitutti, Marja Raekallio, Kati Salla, Erja Kuusela, Ville Ranta-Panula, Valtteri Rinne, Outi Vainio and Mika Scheinin
Drug Metabolism and Disposition March 1, 2012, 40 (3) 445-449; DOI: https://doi.org/10.1124/dmd.111.042671

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Research ArticleArticle

ALTERED DISPOSITION OF DEXMEDETOMIDINE BY MK-467 IN DOGS

Juhana Honkavaara, Flavia Restitutti, Marja Raekallio, Kati Salla, Erja Kuusela, Ville Ranta-Panula, Valtteri Rinne, Outi Vainio and Mika Scheinin
Drug Metabolism and Disposition March 1, 2012, 40 (3) 445-449; DOI: https://doi.org/10.1124/dmd.111.042671
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