A cyclodextrin formulation to improve use of the anesthetic tribromoethanol (Avertinreg;)

Objective: Efficacy and safety concerns have been raised in the literature with the use of tribromoethanol (TBE) (Avertin®) for anesthesia in rats and mice when administered by intraperitoneal (IP) injection. Despite the controversy, it remains in common usage as an anesthetic agent in laboratory rodents for short-term surgical procedures. Cyclodextrins have been shown to improve drug solubility and were investigated here as an improved anesthetic formulation for mice. Materials and Methods: The phase solubility of TBE with hydroxypropyl-β-cyclodextrin (HP-β-CD) was estimated. The efficacy of two anesthetic regimens was compared in this study; the conventional TBE formulation solubilized in tert-amyl alcohol and a HP-β-CD formulation containing TBE. Mice (n = 6) were administered the formulations by IP injection and the pharmacodynamic parameters of time to induction of anesthesia, duration of anesthesia and recovery time were measured using a combined reflex score (CRS). Results and Discussion: Phase solubility studies showed a linear increase in the solubility of TBE with increasing HP-β-CD concentration and suggested >1:1 binding of the drug in the cyclodextrin complex. At a dose of 260 mg/kg the standard TBE formulation appeared to produce deeper anesthesia than the cyclodextrin formulation, with a minimum average CRS of 1.8 compared with 5.2. No post-mortem pathology was observed in mice that received either the conventional or cyclodextrin formulation. Conclusion: The cyclodextrin TBE formulation did not conclusively provide an improved anesthetic response at a dose of 260 mg/kg compared with the conventional formulation. The improved solubility of TBE with HP-β-CD and the reduced variability in anesthetic response warrants the further investigation of this formulation. This study has also identified the value of using the anticholinergic atropine in association with TBE for anesthesia.