The Impact of Vatinoxan on the Concentrations of Medetomidine, Midazolam, and Fentanyl in Central Nervous System After Subcutaneous Co‐Administration in Rats

Our aim was to investigate whether vatinoxan, a peripherally acting alpha₂-adrenoceptor antagonist, would affect the concentrations of medetomidine, midazolam, and fentanyl in the central nervous system after subcutaneous co-administration. Twelve healthy male Wistar rats, aged between 13 and 15 weeks, were used in this study. The animals received one of two subcutaneously administered treatments: medetomidine 0.25 mg/kg, midazolam 2 mg/kg, and fentanyl 0.01 mg/kg (MMF) or MMF with 5 mg/kg of vatinoxan (MMF-V). 15 min later, the sedated rats were humanely euthanized with intravenous pentobarbital. Plasma and tissue, including aliquots of the cortex, thalamus, pons, and lumbar spinal cord, were harvested and analyzed for drug concentrations. The treatments were compared with Bonferroni corrected t-tests after one-way analysis of variance. The concentrations of medetomidine (144 ± 19.4 vs. 107 ± 13.1 ng/g [mean ± 95% confidence interval]) (p = 0.04) and fentanyl (2.3 ± 0.2 vs. 1.7 ± 0.3 ng/g) (p = 0.04) in the cortex were significantly higher in the rats administered MMF-V. Similarly, cortex: plasma drug concentration ratios were significantly higher for medetomidine, midazolam, and fentanyl after MMF-V (p < 0.001 for all). The results confirm that vatinoxan increases early cortical exposure to subcutaneously co-administered medetomidine and fentanyl.