Age‐dependent development of acute tolerance to propofol and its distribution in a pharmacokinetic compartment‐independent rat model

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Abstract
Background:Previous animal and clinical studies have shown a dose‐dependent increase in propofol concentrations in blood at wakening after propofol infusion. A development of an acute tolerance to propofol has been proposed. To elucidate this, brain concentrations of propofol at the time of an EEG end point was used as a measure of CNS sensitivity.Methods:Twenty young or 20 old rats were assigned to either induction of anaesthesia with propofol or induction followed by maintenance of anaesthesia with intermittent propofol infusions during 60 minutes. All rats were killed at the EEG end point and samples of cerebral cortex, hippocampus, striatum, brain stem, cerebellum, blood, muscle and fat tissue were submitted to HPLC analysis of propofol concentrations. A new model describing the infusion requirements is introduced.Results:The estimated infusion rate during maintenance declined exponentially with time at a slower rate in young compared with old rats. Old rats had higher propofol concentrations in blood, hippocampus, striatum, brain stem, cerebellum, muscle and fat after 60 minutes compared with induction. In contrast, young animals had no significant change in brain concentrations, but the propofol concentrations in muscle and fat were increased.Conclusion:It is concluded that maintenance of propofol anaesthesia may alter the CNS sensitivity to propofol in old animals, i.e. an acute tolerance may develop. Young animals do not seem to be capable of developing an acute tolerance to propofol. The results also support previous findings that a redistribution is important for the rapid clearance of propofol from blood.