Kinetics and clinical effects of flurazepam in young and elderly noninsomniacs

Abstract

Twenty-six healthy subjects from 19 to 85 yr old took single 15-mg doses of flurazepam (FLZ). Concentrations of desalkylfurazepam (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 (t1/2) (range, 37 to 289 hr) was longer in elderly than in young men (mean 74 and 160 hr, p less than 0.05), but t1/2 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 less than 0.05), but values were essentially the same in elderly and young women (85 and 86 ng/ml). Single-dose t1/2 correlated with washout t1/2 after termination of FLZ treatment (r = 0.87, P less than 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.

Effect of Aging on Glucuronidation of Valproic Acid in Human Liver Microsomes and the Role of UDP-Glucuronosyltransferase UGT1A4, UGT1A8, and UGT1A10

“…Based on pharmacokinetic studies with benzodiazepines, Greenblatt and coworkers suggested that total body clearance of drugs that are primarily glucuronidated is not affected by aging. (Greenblatt et al, 1980(Greenblatt et al, , 1981a(Greenblatt et al, ,b, 1991aDivoll et al, 1981;Durnas et al, 1990). Our studies with valproate (a general substrate catalyzed by UGT2B7 and several other enzymes) indicate that VPA total body clearance would decline with the age-related decrease in liver mass, assuming that intrinsic clearance is not altered with aging.…”

Age‐related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications

“…Sedation is induced by diazepam at lower doses and lower plasma concentrations in elderly subjects [116,117]. Advancing age is also associated with increased sensitivity to the effects of nitrazepam, flurazepam, and loprazolam [118][119][120]. The exact mechanisms responsible for the increased sensitivity to benzodiazepines with ageing are unknown, however.…”

Absorption and disposition of ibuprofen in the elderly

“…They continued fasting for 3 hours after dosage. Venous blood samples were drawn through an indwelling butterfly cannula (kept patent by a slow infusion of physiologic saline), or by separate venipuncture into heparinized tubes prior to the dose and at the following post-dosage times: 0.25 hours, 0.5, 0.75, 1, 1.5, 2, 2.5, 3,4,6,8,10,12,15,18, and 24 hours. Blood samples were centrifuged, and the plasma separated and frozen until the time of assay.…”