DISPOSITION OF DIAZEPAM IN YOUNG AND ELDERLY SUBJECTS AFTER ACUTE ANDCHRONIC 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 ch ronic oral dosing of diazepam. 2 Following intravenous administration, the half-life and volume of distribution of C-14-labelled diazepam in the elderly were approximately twofold greater than corresponding est imates in younger subjects (mean +/- s.d., 71.5 +/- 27.6 vs 44.5 +/- 1 6.5 h and 1.39 +/- 0.32 vs 0.88 +/- 0.30 1 kg(-1), respectively). Clea rance 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 administ ration. A radioreceptor assay that measured total benzodiazepine activ ity, including diazepam and its active metabolites, indicated that the accumulation of 'benzodiazepine equivalents' was similar to the sum o f 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' conc entration 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 diffe rences 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 +/- 0.1 2 ml min(-1) kg(-1), young vs elderly, multiple-dose) and no age-relat ed differences in the levels of accumulated 'benzodiazepine equivalent s' (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 acu te 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.