Kinetics of drug action in disease states. XXIV. Pharmacodynamics of diazepam and its active metabolites in rats.

The purpose of this investigation was to determine the relative contribution of diazepam and its active metabolites (desmethyldiazepam, oxazepam and temazepam) to the hypnotic activity of this benzodiazepine drug and to assess the role of rate of drug administration as a determinant of the relative concentrations of diazepam and its active metabolites in serum and in the central nervous system at the onset of a predefined pharmacologic endpoint. Rats were given i.v. infusions of diazepam to onset of loss of righting reflex. Samples of cerebrospinal fluid (CSF), blood (for serum) and brain were obtained at that time and were analyzed for diazepam and its active metabolites. Based on the results of six experiments on groups of 6 to 14 rats performed at the same time of day over 11 months, the pharmacologic response of the animals was found to be relatively consistent, with little variation between rats and between experiments in body weight-normalized effective dose and in diazepam serum and CSF concentrations. All three active metabolites of diazepam were found in serum, CSF and brain; they were relatively more prominent in CSF than in serum. Variation of the diazepam infusion rate (four rates between 0.10 and 0.34 mg/min per approximately 200-g rat) was associated with changes in average onset time (50 to 10 min) and dose (26 to 17 mg/kg) required to produce the pharmacologic effect. The drug and metabolite concentrations in CSF determined in these experiments, together with corresponding concentrations obtained by infusion of each active metabolite individually, yielded estimates of their relative hypnotic potency that were unaffected by differences in serum protein binding and tissue distribution.(ABSTRACT TRUNCATED AT 250 WORDS)