Recovery from dispositional and pharmacodynamic tolerance after chronic pentobarbital treatment

Recovery characteristics of dispositional and pharmacodynamic tolerances produced by chronic Na-pentobarbital treatment were studied. To study dispositional tolerance, the rate of disappearance of pentobarbital from blood was estimated by sequential blood sampling before and after chronic treatment and during 15 days of withdrawal after chronic treatment. Pentobarbital half-life values were compared with four representative cytochrome P-450-mediated hepatic microsomal mixed-function oxidase reactions: aminopyrine demethylase, benzo(a)pyrene hydroxylase, 7-ethoxycoumarin deethylase and 7-ethoxyresorufin deethylase and with the concentration of cytochrome P-450 in sequentially biopsied liver samples. Pharmacodynamic tolerance was evaluated by measuring the increase in pentobarbital blood concentration required to produce predetermined central nervous system functional depression ratings. The recovery from dispositional tolerance was more rapid than the recovery from pharmacodynamic tolerance. Thus, whereas cytochrome P-450 levels and pentobarbital elimination rates were increased to close to twice pretreatment values by chronic treatment, by about 2 week post-withdrawal the values had normalized. In contrast, pharmacodynamic tolerance persisted after no residual dispositional tolerance remained. The neuronal functions most sensitive to barbiturate (i.e., sedation and loss of fine motor coordination) exhibited a greater degree of pharmacodynamic tolerance than other functions; hence the recovery of these neuronal functions took a longer period of time for their recovery. However, the rates of recovery of pharmacodynamic tolerance at all levels of central nervous system function seemed relatively constant indicating that there are uniform readaptation mechanisms for all the central nervous systems functions.