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.
Twenty-six healthy subjects from 19 to 85 yr old took single 15-mg doses of flurazepam (FLZ). Concentrations of desalkylflurazepam (DAFLZ), its principal metabolite, were measured by gas-liquid Chromatography in multiple samples drawn 7 or more days after the dose. For the first 6 to 8 hr after drug, several additional FLZ metabolites appeared in plasma, but only DAFLZ was detected from 12 hr onward. Its elimination half-life (t½) (range, 37 to 289 hr) was longer in elderly than in young men (x̄ 74 and 160 hr, p < 0.05), but t½ in young and elderly women was much the same (90 and 120 hr, P = NS). Eighteen of the 26 subjects then received FLZ, 15 mg, nightly for 15 consecutive nights. Blood samples were drawn during FLZ dosage and in the withdrawal period, and morning self-ratings of mood and sleep patterns were obtained using visual analogue scales. DAFLZ cumulation was extensive, with a mean cumulation ratio of 7.5. Mean steady-state plasma levels of DAFLZ were higher in elderly than in young men (81 and 53 ng/ml, P < 0.05), but values were essentially the same in elderly and young women (85 and 86 ng/ml). Single-dose t½ correlated with washout t½ after termination of FLZ treatment (r = 0.87, P < 0.01). Clinical self-ratings indicated increases over time in perception of morning sedation; changes slowly reverted to baseline in the week after dosage. Sleep patterns also improved on FLZ (shortened latency, longer duration, "deeper" sleep). After termination of treatment, sleep parameters returned to baseline with a suggestion of "overshoot" sleep disturbance at days 5 and 7 after drug. There was no evidence of increased sensitivity to FLZ in the elderly. Subjects did not perceive any impairment of intellectual function or motor performance, and no other adverse reactions were reported. Clinical Pharmacology and Therapeutics (1981) 30, 475–486; doi:10.1038/clpt.1981.191
The kinetic properties of three benzodiazepine hypnotics are reviewed. Flurazepam serves as a precursor for at least two rapidly appearing and rapidly cleared metabolites that may contribute to sleep induction and are nonaccumulating. The final metabolite of flurazepam (N-desalkylflurazepam), however, has a long half-life and accumulates during repeated dosage. Temazepam has a relatively slow rate of absorption and an intermediate half-life in the range of 10 to 20 hours. Triazolam has an intermediate rate of absorption; due to its ultrashort half-life (1.5 to 5 hours), triazolam is a non-accumulating hypnotic. Taken together with sleep laboratory studies and clinical trials, knowledge of the kinetic profile of benzodiazepine hypnotics can assist in evaluating their clinical benefits and disadvantages.
Eight healthy volunteers received single intravenous doses of diazepam and lorazepam on two separate occasions. Kinetic parameters of drug distribution and clearance were determined by measurement of multiple plasma concentrations following each dose. Elimination half-life for diazepam averaged 51.2 hr, as compared with 15.7 hr for lorazepam. However, after correction for individual differences in protein binding (mean free fraction 1.5% for diazepam versus 10.1% for lorazepam), the volume of distribution of unbound diazepam (mean 133 liter/kg) was more than 10 times larger than that of lorazepam (mean 12 liter/kg). This is consistent with in vivo measurements of lipid solubility indicating that diazepam has a much larger octanol/water partition coefficient than lorazepam. Thus, the shorter duration of action of a single intravenous dose of diazepam as compared with lorazepam, despite the much longer half-life of diazepam, is explained by the more extensive tissue distribution of unbound diazepam.
