Brain-plasma distribution of free and total benzodiazepines in dogs physically dependent on different doses of diazepam

Steady-state levels of oxazepam (OX), nordiazepam (ND), and diazepam (DZ) in plasma, brain tissue, cerebrospinal fluid (CSF), and intracranial microdialysis perfusate were determined in dogs dependent on 0.56, 4.5, 9, and 36 mg/kg per day of DZ. There was a linear relationship between the total plasma and brain levels of DZ, ND, and OX and the chronic dose of DZ. Levels of free benzodiazepines in plasma and CSF and levels in microdialysis perfusates from plasma and brain were significantly correlated. With increasing dependence on DZ there was progressively more free ND and OX and less free DZ in plasma, CSF, and brain. There was a correlation between several signs of precipitated abstinence and free ND in the brain interstitial fluid, whereas convulsions emerged only when free metabolites exceeded free DZ. The changes in contribution of free DZ, ND, and OX to the overall levels of benzodiazepines present in the CNS may explain differences in signs of abstinence for different levels of dependence on DZ.