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

Abstract

Objective: We determined the possible effects of a peripherally acting alpha2-adrenoceptor antagonist, MK-467, on the absorption of intramuscularly (IM) co-administered medetomidine, butorphanol and midazolam. Study design: Randomized, experimental, blinded cross-over study. Animals: Six healthy Beagle dogs. Methods: Two 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. Results: Data from five dogs were analyzed. Heart rate was significantly higher from 20 until 90 minutes after MBM-MK. The Tmax for midazolam and levomedetomidine (mean ± standard deviation) were approximately halved with co-administration 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 relevance: MK-467 accelerated the absorption of IM co-administered drugs. This is clinically relevant as it may hasten the onset of peak sedative effects.