Abstract

The disposition of diazepam after intravenous administration was investigated in mature young and old female Dutch Belted rabbits (1-1.5 and 5.6.5 years) and Fischer-344 rats (6 and 30 months) to determine whether they exhibited an age-related increase in distribution similar to that previously observed in the human. No significant differences were found in the pharmacokinetic behavior of diazepam or its N,-demethylated metabolite between the young and old rabbits, although there was a suggestion that clearance might have been impaired in the older animals. In contrast, the initial postequilibrium and steady-state volumes of distribution of diazepam were higher in the old rat, but only the latter was statistically significant when adjusted for body weight. No significant differences were found in other pharmacokinetic parameters including plasma binding, nor were the metabolite concentration/time profiles different. The increased steady-state distribution volume could reflect a change in lean body mass/body in the old rat. However, the magnitude of the distributional change (50%) in small fat ratio compared to that in humans (300-400%) and this precludes the female fisher-344 rat as a suitable animal model for further investigation of the effects of age on the distribution of the benzodiazepines.