Clobazam kinetics in the elderly.

Abstract

I The effects of age and sex on the disposition of clobazam (CBZ), a 1 ,5-benzodiazepine derivative, were evaluated in a series of 29 healthy volunteers aged 18 to 72 years, who ingested single 20 mg oral doses. CBZ kinetics were determined from multiple plasma concentrations measured during 7 days after the dose. 2 CBZ was rapidly absorbed, with peak levels reached an average of 1.5 h after dosing (range 0.5-2.5 h). Mean absorption half-life was 19.7 min. Absorption kinetics were not influenced by age or sex. 3 Elimination half-life ranged from 11 to 77 h, and was significantly longer in elderly v young males (48 v 17 h, P < 0.01). In women, half-life also increased with age, but differences between young and elderly women were less striking (31 v 49 h, P < 0.05). 4 Volume of distribution (Vd) was influenced by age and sex. Vd became larger with age regardless of sex, and within each age group was larger in women than in men. Total clearance was unrelated to age in women, but declined significantly with age in men (P < 0.01). 5 The mean free fraction for CBZ in plasma was 11.5% (range 8.6-15.0%), and tended to increase with age, partly due to a significant age-related decline in plasma albumin concentration (r = -0.68, P < 0.001). Correction of Vd and clearance for individual differences in binding did not alter their relation to age and sex. 6 As in the case of other benzodiazepines biotransformed by oxidative pathways, the capacity for N-demethylation of CBZ declines with age in men, but age has a minimal effect on CBZ clearance in women.

The disposition of antipyrine and its metabolites in young and elderly healthy volunteers.

“…The proportions of AP cleared as OHA were virtually identical in the two groups suggesting that there was not simply a general state of relative enzyme induction in the young group but rather a specific defect in demethylation in the elderly. Consistent with this conclusion is the finding that the capacity for N-demethylation of benzodiazepines in elderly men is also reduced (Greenblatt et al, 1981(Greenblatt et al, , 1982a. The alternative possibility, namely that 3-hydroxylation is selectively enhanced in the elderly is not tenable since neither clearance for production of HMA nor AP clearance were increased in the elderly.…”

“…Renal function declines with increasing age resulting in a predictable reduction in elimination of some drugs and their metabolites while the effect of ageing on drug metabolism is less clear. The activity of mixed function oxidative enzymes may decline with age (O'Malley et al, 1971;Irvine et al, 1974;Farah et al, 1977;Greenblatt et al, 1981) but the changes may not be directly attributable to ageing. In a study of 307 healthy male subjects 51 Vestal et al (1975) showed that differences in smoking could partly explain lower clearances and longer half-lives of AP in subjects over 60 years compared with those under 40 years.…”

Reduced clearance of triazolam in old age: relation to antipyrine oxidizing capacity.

“…Previous studies of benzodiazepines biotransformed by oxidative metabolic pathways, including diazepam (Greenblatt et al, 1980a;Ochs et al, 1981), desmethyldiazepam (Allen et al, 1980;Shader et al, 1981) desalkylflurazepam (Greenblatt et al, 1981a), clobazam (Greenblatt et al, 1981b), and alprazolam (Greenblatt et al, 1983b) indicate significantly reduced metabolic clearance and prolonged elimination half-life in elderly as opposed to young male subjects. Age-related changes in metabolizing capacity among women, on the other hand, are small.…”

Responsiveness to oral diazepam in the elderly: relationship to total and free plasma concentrations.

“…The most important findings to emerge have been (i) a reduction in the rate of biotransformation of oxidatively metabolised compounds (especially in males) corresponding to that observed with antipyrine (Greenblatt et *Present address and correspondence: Department of Geriatric Medicine, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN al., 1982), (ii) an increase in the distribution volume of these compounds (Klotz et al, 1975;Shader et al, 1977;MacLeod et al, 1979;Allen et al, 1980;Greenblatt et al, 1981) and (iii) absence of any major effect of age on the rate of elimination of those drugs metabolised via nonoxidative routes, such as conjugation .…”

“…Benzodiazepines are highly protein bound, so that a small reduction in protein binding may lead to the presence of significantly increased concentrations of free (unbound) drug at the receptor site, even allowing for the characteristically large distribution volumes. Reports have conflicted, some studies showing no reduction in protein binding with age (Klotz et al, 1975;Wilkinson, 1978;Greenblatt et al, 1981), others demonstrating a clear and significant reduction (Macklon et al, 1980;Greenblatt et al, 1980;.…”