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

Abstract

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

Quantitative determination of α2B-adrenoceptor-evoked myosin light chain phosphorylation in vascular smooth muscle cells

“…Upon intravenous administration, it produces a transient increase in blood pressure in humans and other mammals (Ebert et al, 2000;Honkavaara et al, 2012;Snapir et al, 2006). Therefore, dexmedetomidine was chosen as the reference agonist to which the effects of other compounds were compared.…”

“…Therefore, central α 2A -adrenoceptors are currently employed as targets of antihypertensive agents (Aantaa & Jalonen, 2006), but vascular α 2 -adrenoceptors have so far not been exploited as cardiovascular drug targets. A peripherally acting subtype-nonselective α 2 -adrenoceptor antagonist was recently shown to effectively counteract the vasoconstriction evoked by the potent α 2 -adrenoceptor agonist dexmedetomidine (Honkavaara et al, 2012). However, chronic subtype-nonselective α 2 -adrenoceptor blockade is likely to lead to adverse cardiovascular effects as a consequence of loss of presynaptic α 2A -autoreceptor function.…”

Effects of MK‐467 on the antinociceptive and sedative actions and pharmacokinetics of medetomidine in dogs

“…In the rat, co‐administration of MK‐467 had no detectable effects on the analgesic activity of dexmedetomidine in a visceral pain model (Ulger et al ., ). However, by counteracting the cardiovascular effects of dexmedetomidine, MK‐467 also influences the disposition of dexmedetomidine and thus decreases its concentration in plasma (Honkavaara et al ., ).…”

The impact of medetomidine on the protein‐binding characteristics of MK‐467 in canine plasma

“…Honkavaara et al . () reported MK‐467 dose‐related plasma concentrations ranging from 1100 to 4280 ng/mL 1 min after intravenous injection, while Kaartinen et al . () reported MK‐467 plasma concentrations in the range 100–800 ng/mL (approximately) during constant rate infusion.…”

“…However, the volume of distribution of MK‐467 has been reported in the dog and dexmedetomidine had no impact on the disposition of MK‐467 or its clearance when the two drugs were co‐administered (Honkavaara et al ., ). Comparison of dose‐corrected values of area under the curve (AUC) were equivalent for MK‐467 at 250 and 500 μg/kg, with no further increase in exposure at the higher dose of 750 μg/kg IV (Honkavaara et al ., ). Based on these AUC data, it seems unlikely that large fluctuations in unbound drug fraction would occur in vivo .…”