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.

The impact ofMK‐467 on plasma drug concentrations, sedation and cardiopulmonary changes in sheep treated with intramuscular medetomidine and atipamezole for reversal

“…In the present study, the plasma concentrations of medetomidine's enantiomers were nearly identical. This is in contrast to the findings in dogs (Bennett, Salla, Raekallio, Scheinin, & Vainio, 2017;Bennett et al, 2016), where DEX concentrations were significantly higher than those of LEV. In dogs, the clearance of LEV was significantly higher than that of DEX after administration of racemic medetomidine (Bennett et al, 2016), whereas in sheep, the clearance of the enantiomers may be less different.…”

Peripheral α2-adrenoceptor antagonism affects the absorption of intramuscularly coadministered drugs

“…Therefore the slightly but significantly deeper overall sedation with MK-467 during the first 15 minutes (AUC sed0-15 ) probably reflected the higher plasma drug concentrations at that time. Although the racemic medetomidine contains 50% of both enantiomers, in plasma the dexmedetomidine concentration was substantially higher than that of levomedetomidine, as also earlier reported in dogs (Bennett et al 2016). As Kuusela et al (2000) confirmed that levomedetomidine is relatively inactive in producing effects typical to alpha 2adrenoceptor agonists the ratio of the enantiomers in plasma favoring dexmedetomidine is likely to attribute to the level of sedation.…”

“…As we were particularly interested in the absorption phase, the follow-up period was short and no elimination phase of these drugs was observed. Thus we do not report or comment on half-lives or clearance, although it has been demonstrated that MK-467, to some extent, increases the clearance of dexmedetomidine, probably because of preserved liver blood flow (Honkavaara 2012;Bennett et al 2016). For the same reasons, we reported AUC 0-90 for drug concentrations in plasma which were calculated based on the observed data.…”

“…Furthermore, Bennett et al (2016) reported that after IV administration of medetomidine in dogs, the levomedetomidine concentration in plasma was significantly lower than that of dexmedetomidine. Therefore, analyzing plasma medetomidine concentrations in dogs may not reflect the actual concentrations of the stereoisomers.…”

Concentrations of medetomidine enantiomers and vatinoxan, an α2-adrenoceptor antagonist, in plasma and central nervous tissue after intravenous coadministration in dogs

“…In brief, vatinoxan has been shown to either attenuate or prevent the cardiovascular effects of various α 2 -adrenoceptor agonists in dogs (Pagel et al 1998;Enouri et al 2008;Honkavaara et al 2008Honkavaara et al , 2011Rolfe et al 2012), horses (Bryant et al 1998;de Vries et al 2016;Tapio et al 2018), sheep (Bryant et al 1998;Raekallio et al 2010: Adam et al 2018) and cats (Pypendop et al 2017a;Siao et al 2017). Moreover, its impact on agonistinduced sedation appears to be minor and more related to alteration on the disposition of coadministered agonists drugs through attenuation of their cardiovascular effects (Vainionpaa et al 2013;Bennett et al 2016;Restitutti et al 2017;Adam et al 2018;Pypendop et al 2016Pypendop et al , 2017bHonkavaara et al 2017a, b). However, to date, direct evidence of the inability of vatinoxan to cross the mammalian blood-brain barrier in vivo only exists for rats and marmosets (Clineschmidt et al 1988).…”