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

: Bennett RC, Salla KM, Raekallio MR, Hanninen L, Rinne VM, Scheinin M, Vainio OM

Publisher: WILEY-BLACKWELL

: 2016

: Journal of Veterinary Pharmacology and Therapeutics

: JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS

: J VET PHARMACOL THER

: 39

: 4

: 336

: 343

: 8

: 0140-7783

DOI: https://doi.org/10.1111/jvp.12292

We investigated the influence of the peripherally acting alpha(2)-adrenoceptor antagonist MK-467 on the sedative and antinociceptive actions and plasma drug concentrations of medetomidine, an alpha(2)-adrenoceptor agonist that is used in veterinary medicine as a sedative and analgesic agent. Eight healthy beagle dogs received intravenous medetomidine (10 mu g/kg) or medetomidine with MK-467 (250 mu g/kg) in a randomized crossover design. A standardized nociceptive pressure stimulus was applied to a nail bed of a hindlimb. Times for withdrawal of the limb and for head lift were measured, and sedation was scored. EEG data were collected prior to and after stimulation. Plasma drug concentrations were measured. Co-administration of MK-467 significantly attenuated medetomidine analgesia, as assessed with limb withdrawal, and also shortened the duration of sedation. The apparent plasma clearance of both enantiomers of medetomidine, dexmedetomidine and levomedetomidine, was more than doubled in the presence of MK-467. Antagonism by MK-467 of medetomidine-evoked vasoconstriction is seen as the mechanism behind this pharmacokinetic drug interaction. Thus, MK-467 attenuated the antinociceptive and sedative effects of medetomidine. This can probably be explained by increased clearance and decreased concentrations of dexmedetomidine in plasma after co-administration of MK-467 with racemic medetomidine.