| Abstract: | 1 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 of 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 less than 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 less than 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 less than 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 less than 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. |
