Disposition of diazepam in young and elderly subjects after acute and chronic dosing

1. The pharmacokinetics of diazepam were examined in seven young (20-30 years) and six elderly (60-75 years) males prior to and also after chronic oral dosing of diazepam. 2. Following intravenous administration, the half-life and volume of distribution of 14C-labelled diazepam in the elderly were approximately twofold greater than corresponding estimates in younger subjects (mean +/- s.d., 71.5 +/- 27.6 vs 44.5 +/- 16.5 h and 1.39 +/- 0.32 vs 0.88 +/- 0.30 1 kg-1, respectively). Clearance did not differ between the two groups (0.26 +/- 0.09 vs 0.29 +/- 0.09 ml min-1 kg-1). 3. The accumulation of diazepam and its major metabolite, desmethyldiazepam, were extensive during chronic administration. A radioreceptor assay that measured total benzodiazepine activity, including diazepam and its active metabolites, indicated that the accumulation of 'benzodiazepine equivalents' was similar to the sum of the accumulated diazepam and desmethyldiazepam concentration levels. However, the level of 'benzodiazepine equivalents' on multiple-dosing was about double that of the predicted steady-state 'equivalent' concentration from single-dose studies. This was due to the insensitivity of the radioreceptor assay for desmethyldiazepam following single-dose diazepam administration. 4. There were no age- or dosing-related differences in diazepam clearance (0.37 +/- 0.22 vs 0.32 +/- 0.18 ml min-1 kg-1, young vs elderly, single-dose; 0.37 +/- 0.11 vs 0.27 +/- 0.12 ml min-1 kg-1, young vs elderly, multiple-dose) and no age-related differences in the levels of accumulated 'benzodiazepine equivalents' (243.7 +/- 60.1 vs 288.0 +/- 125.8 ng ml-1, young vs elderly). 5. Thus, changes that occur in diazepam disposition with ageing after acute administration do not appear to be important during chronic dosing. On the other hand, accumulation of diazepam and desmethyldiazepam are considerable and would be expected to be clinically relevant.