Evaluation and comparison of the pharmacokinetic and pharmacodynamic properties of allopregnanolone and pregnanolone at induction of anaesthesia in the male rat.

We have evaluated and compared the pharmacokinetic and pharmacodynamic properties of allopregnanolone and pregnanolone at induction of anaesthesia in male rats. A threshold method was used, and the first burst suppression period of 1 s or more in the EEG was selected as the end-point after fairly slow infusions. An optimal dose of 4.0 mg kg(-1) min(-1) was noted for both steroids. Brain concentrations were low at low infusion rates, indicating that acute tolerance was not occurring. Significant positive correlations were noted between dose rate and serum concentrations of allopregnanolone (r = 0.94, P<0.001) and pregnanolone (r = 0.88, P<0.001). Such correlations were also seen in striatum, cerebellum, cortex and muscle for both steroids (P<0.01). Despite changing infusion rates, the concentrations of both steroids in brainstem, hippocampus and fat remained stable. Because no correlation between infusion rate and steroid concentration was noted in the brainstem and hippocampus, these two brain areas may be regarded as primary sites of action for allopregnanolone and pregnanolone. Pregnanolone concentrations in the brainstem and hippocampus were significantly higher than those of allopregnanolone, suggesting that allopregnanolone was more potent than pregnanolone in inducing anaesthesia.