ACUTE TOLERANCE TO DIAZEPAM IN MICE: PHARMACOKINETIC CONSIDERATIONS

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Abstract
SUMMARY: 1. 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.2. 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).3. 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.4. It is concluded that acute tolerance to diazepam in mice may not be attributed to changes in pharmacokinetic factors.