RT Journal Article SR Electronic T1 Influence of MK-467, a Peripherally Acting α2-Adrenoceptor Antagonist on the Disposition of Intravenous Dexmedetomidine in Dogs JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 445 OP 449 DO 10.1124/dmd.111.042671 VO 40 IS 3 A1 Juhana Honkavaara A1 Flavia Restitutti A1 Marja Raekallio A1 Kati Salla A1 Erja Kuusela A1 Ville Ranta-Panula A1 Valtteri Rinne A1 Outi Vainio A1 Mika Scheinin YR 2012 UL http://dmd.aspetjournals.org/content/40/3/445.abstract 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.