PT  - JOURNAL ARTICLE
AU  - Juhana Honkavaara
AU  - Flavia Restitutti
AU  - Marja Raekallio
AU  - Kati Salla
AU  - Erja Kuusela
AU  - Ville Ranta-Panula
AU  - Valtteri Rinne
AU  - Outi Vainio
AU  - Mika Scheinin
TI  - Influence of MK-467, a Peripherally Acting α<sub>2</sub>-Adrenoceptor Antagonist on the Disposition of Intravenous Dexmedetomidine in Dogs
AID  - 10.1124/dmd.111.042671
DP  - 2012 Mar 01
TA  - Drug Metabolism and Disposition
PG  - 445--449
VI  - 40
IP  - 3
4099  - http://dmd.aspetjournals.org/content/40/3/445.short
4100  - http://dmd.aspetjournals.org/content/40/3/445.full
SO  - Drug Metab Dispos2012 Mar 01; 40
AB  - 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.