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

• DOI: 10.1124/dmd.111.042671
• Publication Date: 2011-11-24T06:01:14Z
• Authors: Juhana Honkavaara; Flavia Restitutti; Marja Raekallio; Kati Salla; Erja Kuusela; Ville Ranta-Panula; Valtteri Rinne; Outi Vainio; Mika Scheinin
• Keywords: Male; Dose-Response Relationship, Drug; Hemodynamics; 04 agricultural and veterinary sciences; Adrenergic alpha-2 Receptor Antagonists; ta3111; 3. Good health; 0403 veterinary science; Dogs; Anesthesia, Intravenous; Animals; Hypnotics and Sedatives; Drug Interactions; Female; Dexmedetomidine; Quinolizines

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 α(2)-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 α(2)-adrenoceptor antagonist MK-467 markedly influenced the early disposition of dexmedetomidine without obvious effects on the later plasma concentrations of the drug.