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

Abstract

MK-467 accelerated the absorption of IM coadministered drugs. This is clinically relevant as it may hasten the onset of peak sedative effects.

Clinical pharmacokinetics of a dexmedetomidine–methadone combination in dogs undergoing routine anaesthesia after buccal or intramuscular administration

“…Although this result may be influenced by the limitation observed in the IM group, where the first sampling times were taken at variable times, that may have hindered the evaluation of a real absorption in the first 30 min after administration, the presence of higher drugs concentrations and AUCs after IM route agrees with the studies reported byPorters et al (2014) andWells et al (2008). Moreover, the IM route showed a tendency of a longer T max (p > 0.05) for MET than DEX (30 vs. 20 min, respectively), resulting in an agreement with data reported byKallio-Kujala et al (2018).Clearly, the induction and maintenance of general anaesthesia may have influenced the kinetic profile of DEX and MET for both routes of administration. In fact, the variability in the drugs serum concentrations was particularly observed during the anaesthetic period(Figures 1 and 2), to support a probable effect on the two molecules' redistribution, anyway difficult to explain in this clinical pharmacokinetic study.…”

“…These results were explained with the same hypotheses, (high administration volume, ptyalism and peripheral vasoconstriction). Additionally, DEX‐induced peripheral vasoconstriction was also observed by other authors in IM route of administration (Kallio‐Kujala et al, ; Pypendop, Honkavaara, & Elkiw, ).…”

“…Certainly, a hypothesis might be due to the lower absorption of both drugs by OTM route. Finally, considering the two molecules singularly, during the anaesthetic period MET seems to have manifested a greater variability, almost to reconfirm the hypothesis of the DEX‐induced influence on its disposition and redistribution (Kallio‐Kujala et al, ; Pypendop et al, ). However, the relatively short duration of the anaesthetic period (approximately 1 hr, Figures and ) should have only partially influenced the pharmacokinetic profiles of DEX and MET following the two routes of administration.…”

“…These results were explained with the same hypotheses, (high administration volume, ptyalism and peripheral vasoconstriction). Additionally, DEX-induced peripheral vasoconstriction was also observed by other authors in IM route of administration(Kallio-Kujala et al, 2018;Pypendop, Honkavaara, & Elkiw, 2017).The IM route of administration was used in this study compared to OTM because the former represents a more common route of administration with a large application in the clinical practice. The small IM sample size used (reduced by unrelated medical problems) may be appropriate for pharmacokinetic modelling, although a larger sample of the canine population would have provided more powerful results by lowering the inter-subject variability.…”

“…Finally, another important factor that could have hindered the systemic absorption of DEX and MET was the peripheral vasoconstriction produced by DEX itself due to the interaction with the precapillary sphincter α-2B receptors of the peripheral vascular beds (Murrell & Hellebrekers, 2005), which leads to a reduction in peripheral drug absorption (Kallio-Kujala et al, 2018;Porters et al, 2014).…”