title: Effects of MK-467 on the antinociceptive and sedative actions and pharmacokinetics of medetomidine in dogs.
abstract: We investigated the influence of the peripherally acting α2 -adrenoceptor antagonist MK-467 on the sedative and antinociceptive actions and plasma drug concentrations of medetomidine, an α2 -adrenoceptor agonist that is used in veterinary medicine as a sedative and analgesic agent. Eight healthy beagle dogs received intravenous medetomidine (10 μg/kg) or medetomidine with MK-467 (250 μg/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.
authors.affiliation: University Veterinary Hospital, UCD, Dublin, Ireland.|Department of Equine and Small Animal Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: R C
authors.initials: RC
authors.lastname: Bennett
authors.affiliation: Department of Equine and Small Animal Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: K M
authors.initials: KM
authors.lastname: Salla
authors.affiliation: Department of Equine and Small Animal Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: M R
authors.initials: MR
authors.lastname: Raekallio
authors.affiliation: Department of Production Animal Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: L
authors.initials: L
authors.lastname: Hänninen
authors.affiliation: Department of Pharmacology, Drug Development and Therapeutics, University of Turku and Unit of Clinical Pharmacology, Turku University Hospital, Turku, Finland.
authors.forename: V M
authors.initials: VM
authors.lastname: Rinne
authors.affiliation: Department of Pharmacology, Drug Development and Therapeutics, University of Turku and Unit of Clinical Pharmacology, Turku University Hospital, Turku, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Scheinin
authors.affiliation: Department of Equine and Small Animal Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: O M
authors.identifier: http://orcid.org/0000-0003-3467-2246
authors.initials: OM
authors.lastname: Vainio
mesh_terms: D000700:Analgesics / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D004285:Dogs; D004347:Drug Interactions; D004569:Electroencephalography / Q000187:drug effects / Q000662:veterinary; D005260:Female; D006993:Hypnotics and Sedatives / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D020926:Medetomidine / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D010147:Pain Measurement / Q000662:veterinary; D011807:Quinolizines / Q000494:pharmacology*
chemical_list: D000700:Analgesics; D006993:Hypnotics and Sedatives; D011807:Quinolizines; C055732:vatinoxan; D020926:Medetomidine