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

Abstract

ObjectiveWe determined the possible effects of a peripherally acting α2-adrenoceptor antagonist, MK-467, on the absorption of intramuscularly (IM) coadministered medetomidine, butorphanol and midazolam. Study designRandomized, experimental, blinded crossover study. AnimalsSix healthy Beagle dogs. MethodsTwo IM treatments were administered: 1) medetomidine hydrochloride (20 μg kg–1) + butorphanol (100 μg kg–1) + midazolam (200 μg kg–1; MBM) and 2) MBM + MK-467 hydrochloride (500 μg kg–1; MBM–MK), mixed in a syringe. Heart rate was recorded at regular intervals. Sedation was assessed with visual analog scales (0–100 mm). Drug concentrations in plasma were analyzed with liquid chromatography–tandem mass spectrometry, with chiral separation of dex- and levomedetomidine. Maximum drug concentrations in plasma (Cmax) and time to Cmax (Tmax) were determined. Paired t-tests, with Bonferroni correction when appropriate, were used for comparisons between the treatments. ResultsData from five dogs were analyzed. Heart rate was significantly higher from 20 to 90 minutes after MBM–MK. The Tmax values for midazolam and levomedetomidine (mean ± standard deviation) were approximately halved with coadministration of MK-467, from 23 ± 9 to 11 ± 6 minutes (p = 0.049) for midazolam and from 32 ± 15 to 18 ± 6 minutes for levomedetomidine (p = 0.036), respectively. Conclusions and clinical relevanceMK-467 accelerated the absorption of IM coadministered drugs. This is clinically relevant as it may hasten the onset of peak sedative effects.