Acute tolerance to diazepam in mice: pharmacokinetic considerations.

The tolerance to the hypnotic effect of diazepam developed after a single exposure to diazepam in the presence or absence of cycloheximide, which blocks liver enzyme induction, was studied. At the high dose (30-35 mg/kg) used in this study, diazepam was found to be metabolized very rapidly in mice, consistent with previous findings using a much smaller dose (5 mg/kg). There was no significant difference in the pharmacokinetics of diazepam in control and tolerant mice as observed by monitoring the plasma and brain concentrations of diazepam and N-desmethyldiazepam. It is concluded that acute tolerance to diazepam in mice may not be attributed to changes in pharmacokinetic factors.