Distribution of diazepam,nordiazepam, and oxazepam between brain extraneuronal space,brain tissue,plasma, and cerebrospinal fluid in diazepam and nordiazepam dependent dogs

The compartmental distribution of diazepam (DZ) and nordiazepam (ND) and their metabolites was studied in DZ and ND dependent dogs. The levels of DZ, and ND and their metabolites were determined during the last week of stabilization in the extraneuronal brain space, in brain tissue, in plasma and in CSF. In these studies dependent dogs were anesthetized with pentobarbital and microdialysis probes were inserted bilaterally into the parietal cortex and perfused with artificial cerebrospinal fluid. Microdialysis probes were also used to determine the unbound parent drugs and their metabolites in plasma. The brain-plasma distribution of total ND and oxazepam (OX) is about equal in ND dependent dogs but in DZ dependent dogs total ND and OX are about 2-fold higher in brain than in plasma. The levels of DZ, ND, and OX in the extraneuronal brain space are similar to their unbound levels in plasma. These data suggest that the concentration of free benzodiazepines in plasma is a good approximation of the concentration in the vicinity of the membrane receptors in the dependent dogs.