Thirty-two male and female volunteers, 24-84 years of age, ingested single 30-mg doses of temazepam, a 3-hydroxy-1,4-benzodiazepine derivative used as a hypnotic agent. Kinetics of total and unbound temazepam were determined from multiple plasma temazepam concentrations measured during 48 hr after the dose. The temazepam elimination half-life ranged from 8 to 38 hr and was longer in women than in men (16.8 versus 12.3 hr, p less than 0.05). Likewise, clearance of total temazepam (assuming complete absorption) was higher in men than in women (1.35 versus 1.02 ml/min/kg, p less than 0.025). Neither half-life nor clearance was significantly related to age. The volume of distribution of total temazepam (mean 1.40 liters/kg) was unrelated to age or gender. Temazepam was extensively protein bound, with a mean free fraction of 2.6% (range 12.7-3.4%). The free fraction increased with age (r = 0.45, p = 0.01), partly due to the inverse relation of the free fraction to plasma albumin concentration (r = -0.34, p = 0.06) and the age-related decline in plasma albumin (r = -0.49, p less than 0.005). After correction for individual differences in binding, clearance of unbound temazepam in men was higher than in women (50.5 versus 39.7 ml/min/kg, 0.05 less than p less than 0.01), and it tended to decline with age in both sexes (r = -0.44 and -0.43, respectively, p = 0.1).

Adult↗

PubMed1981

Benzodiazepine overdosage: plasma concentrations and clinical outcome.

Plasma concentrations and their relation to clinical outcome were evaluated in 21 patients who reached emergency treatment facilities following acute overdosage with benzodiazepine derivatives. Diazepam was implicated in 18 of the 21 cases, with plasma diazepam levels ranging from 585-8,635 ng/ml. In four cases of overdosage with diazepam alone, patients were minimally sedated and were discharged within 24 h, despite diazepam doses as high as 750 mg and plasma levels as high as 4,792 ng/ml. However, concurrent ingestion of diazepam together with other central depressant drugs (such as ethanol, barbiturates, analgesics, or tricyclic antidepressants) produced serious intoxication in 5 of the remaining 14 patients, regardless of the diazepam dosage or plasma concentration. Thus the severity of poisoning following benzodiazepine overdosage is determined largely by co-ingestion of other central depressants rather than the amount of benzodiazepine ingested or its concentration in plasma.

Adolescent↗

PubMed1981

Effect of age and sex on disposition of desmethyldiazepam formed from its precursor clorazepate.

Desmethyldiazepam (DMDZ) disposition was evaluated in 32 healthy male and female volunteers who ingested single 15-mg doses of the precursor compound, clorazepate dipotassium. DMDZ concentrations were measured in multiple plasma samples obtained between 7 and 9 days after dosage. Appearance of DMDZ in blood was rapid, with peak concentrations attained on average 1.5 h after dosage. Absorption half-life (t1/2 a) averaged 24 min. Neither peak time nor t1/2 a were influenced by age or sex. After a rapid phase of distribution, DMDZ elimination was slow, with a mean elimination half-life (t1/2 beta) of 82 h (range 27-219 h). t1/2 beta became prolonged with age in men but not in women. Likewise, clearance of total (free bound) DMDZ declined with age in male subjects (r=- 0.47, P less than 0.1), but was unrelated to age in women. DMDZ was extensively bound to protein in all subjects. The mean free fraction (FF) was 3.1% (range 2.0-4.3%), and increased significantly with declining plasma albumin concentrations (r=-0.57, P less than 0.001). Partly due to a decline in plasma albumin with age (r=-0.47, P less than 0.01), FF tended to increase with age (r=0.23). After correction for individual differences in FF, clearance of pharmacologically active unbound DMDZ declined significantly with age in men (r=-0.65, P less than 0.01), but actually was slightly higher in elderly as opposed to young women. Thus, the age-related decline in the capacity for hepatic hydroxylation of DMDZ is highly sex-specific.

Adult↗

PubMed1981

Binding of diazepam and desmethyldiazepam to plasma protein: concentration-dependence and interactions.

The binding of diazepam (DZ) and its major metabolite desmethyldiazepam (DMDZ) to plasma protein was evaluated in a series of controlled in vitro studies using equilibrium dialysis. Free fraction (FF) of both drugs alone changed significantly with total plasma drug concentration, but the increased FF (reduction in binding) did not occur until concentrations considerably exceeded those encountered during typical therapeutic use. Increasing concentrations of one drug at a time tended to increase FF for the other, although the effects were, at most, of borderline significance. Simultaneously increasing concentrations of both drugs led to significantly increased FF for both. Thus, DZ and DMDZ appear to bind to the same site or sites on plasma albumin. Binding is concentration-independent within and considerably above the usual therapeutic range.

Binding, Competitive↗

PubMed1981

Kinetics and clinical effects of flurazepam in young and elderly noninsomniacs.

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.

Adult↗

PubMed1981

Kinetics of oxazepam and lorazepam in two subjects with Gilbert syndrome.

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Adult↗

PubMed1981

Clobazam kinetics in the elderly.

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.

Adolescent↗

PubMed1981

Diazepam kinetics in patients with renal insufficiency or hyperthyroidism.

1 Eight patients with end-stage renal insufficiency on maintenance haemodialysis, and seven patients with newly diagnosed hyperthyroidism, received a single intravenous dose of diazepam, followed by blood sampling over the next 7 days. Fifteen healthy volunteer controls, matched with patients for age and sex, were similarly studied. 2 Diazepam half-life in renal failure patients (mean 37 h) was greatly reduced compared to controls (mean 92 h, P less than 0.05) and clearance of total (free plus bound) diazepam correspondingly increased (0.94 v 0.34 ml min-1 kg-1, P less than 0.01). 3 However, differences were largely related to disease-related changes in drug binding and distribution. Mean unbound fraction of diazepam in plasma of renal patients (7.0%) was greatly increased over controls (1.4%, P less than 0.01) and Vd of unbound diazepam greatly reduced (57 v 157 l/kg, P less than 0.01). 4 Clearance of pharmacologically active unbound diazepam (intrinsic clearance) was not significantly different between renal patients and controls (23 vs 30 ml min-1 kg-1). 5 None of the kinetic variables for total or unbound diazepam in thyrotoxic patients differed significantly from those in controls matched for age and sex. 6 End-stage renal failure (or its associated drug therapy) alters diazepam protein binding and distribution, but does not significantly change clearance of unbound drug. Thyrotoxicosis does not influence diazepam kinetics.

Diazepam↗

PubMed1981

Benzodiazepines: a summary of pharmacokinetic properties.

1 The onset and duration of action of benzodiazepines after single oral doses depend largely on absorption rate and extent of distribution, respectively. 2 The rate and extent of accumulation during multiple dosage depend on elimination half-life and clearance. A framework is proposed for classification of benzodiazepines according to elimination half-life. 3 Long-acting benzodiazepines have half-life values usually exceeding 24 hours. Drugs in this category have long-acting pharmacologically active metabolites (often desmethyldiazepam), accumulate extensively during multiple dosage, and may have impaired clearance in the elderly and those with liver disease. 4 Intermediate and short-acting benzodiazepines have half-life values from 5-24 hours. Active metabolites are uncommon. Accumulation during multiple dosage is less extensive than with the long-acting group, and diminishes as the half-life becomes shorter. Age and liver disease have a small influence on metabolic clearance. 5 The half-life of ultrashort acting benzodiazepines is less than 5 hours. These drugs are essentially non-accumulating. 6 Pharmacokinetic classification may assist in understanding of differences among benzodiazepines, but does not explain all of their clinical actions.

Anti-Anxiety Agents↗

PubMed1981

Alcohol does not enhance diazepam absorption.

A single 5-mg oral dose of diazepam was administered to 6 healthy volunteers on 3 occasions in a randomized 3-way crossover study. Modes of administration were: (A) (control): diazepam with 120 ml of water, preceded 30 min before with 120 ml of water; (B) diazepam with 120 ml water, preceded by 120 ml of a 50:50 vodka:water mixture, and (C) diazepam with 120 ml of the vodka mixture, preceded by 120 ml of water. Peak plasma diazepam levels averaged 166, 140 and 145 ng/ml in trials A, B and C, respectively; the time of peak concentration was 0.71, 2.1 and 1.5 h after the dose, respectively. Differences were not significant. Total areas under the plasma concentration curve were nearly identical (2.7, 2.8 and 2.9 micrograms/ml X h) among the 3 trials, as were values of diazepam elimination half-life (29, 36 and 35 h). The rate and extent of desmethyldiazepam formation also did not differ among trials. Thus, coadministration of diazepam with or shortly after a typical social cocktail tends to slow the rate of diazepam absorption, but does not influence the completeness of absorption or the rate of elimination.

Absorption↗

PubMed1981

Diazepam kinetics in relation to age and sex.

27 male volunteers aged 20 to 91 years, and 13 female volunteers aged 21 to 33 years, received single 5 to 10 mg doses of diazepam intravenously. Diazepam pharmacokinetics were determined from concentrations measured in multiple plasma samples drawn during 7 days after each dose. Diazepam elimination half-life among males (mean: 66 h) increased significantly with age (r = 0.53, p less than 0.005). Volume of distribution (mean: 1.39 liters/kg) also increased significantly with age (r = 0.67, p less than 0.001). Clearance of total diazepam in males (mean: 0.42 ml/min/kg) tended to decline with age (r = 0.32), but the association was of borderline significance (p = 0.1). Diazepam was extensively bound to plasma protein, with a mean free fraction among male subjects of 1.34%. Free fraction tended to increase with age (r = 0.14). Correction of volume of distribution and clearance for individual differences in binding did not alter the conclusions. Compared to young males, young females had larger volumes of distribution (1.87 vs. 1.34 liters/kg) and higher total clearance (0.63 vs. 0.49 ml/min/kg). These differences were even greater after correction for sex-related changes in protein binding. Elimination half-life did not differ between sexes. Since both age and sex can influence diazepam disposition, both should be considered as independent variables in studies of diazepam pharmacokinetics.

Adult↗

PubMed1981

Alterations in drug distribution and clearance due to obesity.

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Adult↗

PubMed1980

Oxazepam kinetics: effects of age and sex.

Thirty-eight healthy male and female volunteers, 22 to 84 years of age, ingested single 30-mg doses of oxazepam tablets in the fasting state. Oxazepam plasma concentrations were determined by electron-capture gas-liquid chromatography in multiple samples drawn during 48 hr after the dose. Absorption of oxazepam was relatively slow with peak plasma levels reached an average of 2 to 3 hr after dosage. First-order absorption was observed in only 22 of the 38 subjects. Elimination half-life ranged from 4.9 to 19.4 hr and was longer (P < .05) in females (mean: 9.7 hr) than in males (7.8 hr). Half-life was not associated with age in males but tended to increase with age in females (r = 0.45). Oxazepam was extensively bound to plasma protein. The mean free fraction was 4.3% and did not differ between sexes. Free fraction tended to increase with age (r = 0.25), in part because of significantly lower plasma albumin concentrations in the elderly (r = -0.58). Assuming 100% systemic availability, clearance of total as well as unbound oxazepam was significantly greater in men than in women. Intrinsic clearance tended to decline with age in men (r = -0.21) and women (r = -0.24) but these associations were not significant. Higher oxazepam clearance was associated with heavy cigarette smoking but this did not explain the sex-related difference. Thus, sex is a more important determinant of oxazepam clearance than is age.

Adult↗

PubMedDate not supplied

Effect of food on acetaminophen absorption in young and elderly subjects.

Twenty-four healthy volunteers aged 22 to 78 years received 650-mg doses of acetaminophen (AAP) on five separate occasions. The modes of administration were: intravenous AAP by 5-minute infusion; oral AAP as two 325-mg tablets in the fasting state; oral AAP 650 mg as an elixir preparation in the fasting state; tablets with food; and elixir with food. Plasma concentrations of AAP were determined by high-pressure liquid chromatography for up to 12 hours after the dose. In both the young and the elderly groups, the four oral modes of administration were significantly different with respect to peak plasma concentration (P less than 0.001), time to peak plasma concentration (P less than 0.001), and systemic availability (P less than 0.01). Although food slowed the rate of absorption of both oral preparations, no significant difference in peak acetaminophen plasma concentration or time of peak concentration was observed as a function of age. Absolute systemic availability of elixir and tablets in the fasting state tended to be lower in the elderly subjects (P less than 0.05). However, when either preparation was coadministered with food, there were no differences between the two age groups. Thus, age as such does not appear to be a critical determinant in the design of oral acetaminophen dosage schedules.

Absorption↗