Plasma Desmethyldiazepam Research Articles

Age-related changes in the pharmacokinetic disposition of diazepam in foals

Abstract Objective To evaluate changes in the pharmacokinetic disposition of diazepam in foals from 4 to 84 days of age. Sample Population 4 male and 2 female full-term mixed-breed foals. Procedure Diazepam terminal half-life, volume of distribution, clearance, free fraction, unbound volume of distribution, free clearance, peak desmethyldiazepam concentration, and area under the desmethyldiazepam concentration-time curve were determined after IV administration of 0.25 mg of diazepam/kg of body weight to foals at 4, 21, 42, and 84 days of age. Results Disposition of diazepam was best described using a two-compartment model. Clearance and free fraction values (mean ± SEM) determined at 4 days (5.06 ± 0.79 and 51 ± 8 ml/kg/min, respectively) were significantly less than those obtained at 21 (8.64 ± 0.95 and 87 ± 11 ml/kg/min), 42 (7.31 ± 0.82 and 83 ± 10 ml/kg/min), and 84 (8.41 ± 0.56 and 100 ± 12 ml/kg/min) days. Volume of distribution and unbound volume of distribution values determined at 4 days (1.57 ± 0.11 and 16.0 ± 1.7 L/kg, respectively) were significantly less than those found at 21 (2.66 ± 0.33 and 26.8 ± 3.9 L/kg), 42 (3.00 ± 0.42 and 33.9 ± 5.0 L/kg), and 84 (2.55 ± 0.35 and 30.2 ± 5.3 L/kg) days. Peak plasma desmethyldiazepam concentration obtained at 4 days (22.7 ± 2.4 ng/ml) was significantly lower than that obtained at 21 (36.1 ± 4.5 ng/ml), 42 (38.3 ± 4.8 ng/ml), and 84 (34.6 ± 2.1 ng/ml) days. Conclusions Factors likely to affect the pharmacokinetic disposition of diazepam in foals, such as body composition and hepatic enzyme activity, are in transition during the first 21 days of life. These have opposing effects on diazepam clearance and volume of distribution so that terminal half-life remains unchanged. However, clearance determines whether diazepam will accumulate with repeated doses, and care should be taken when administering repeated doses to foals < 21 days old. (Am J Vet Res 1997;58:878–880)

The Kinetic and Dynamic Characteristics of Benzodiazepines in the Treatment of Anxiety

SummaryBenzodiazepines are assumed to cause drowsiness and sedation. Rating scales such as the Massachusetts General Hospital Sedation Scale and the Morning Evaluation of Drug Induced Sedation Scale allow testing of this hypothesis and assessment of the effects of benzodiazepines. We performed a five-week study of prazepam in 63 anxious outpatients. Plasma levels of desmethyldiazepam were assessed weekly. Placebo was given the first week, followed by active drug for three weeks, and placebo the final week. One group received prazepam 30 mg/h, the other received prazepam 10 mg three times per day. Drowsiness-sedation and anxiolytic efficacy were assessed at baseline and weekly. Plasma desmethyldiazepam levels were similar in both treatment groups. Efficacy was profound in both groups. Drowsiness-sedation measured high at baseline and decreased significantly (P=0.05) over the 3 weeks when active drug was administered. Sedation decreased by as much as 40%. Sleep was improved with prazepam, and this may have resulted in decreased drowsiness. We conclude that anxious outpatients have significant levels of drowsiness-sedation and that treatment with benzodiazepines reduces the occurrence of this symptom.

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

The immediate and residual response to single doses of oral diazepam 10 mg was measured in 11 young and 12 elderly healthy volunteers using postural sway, digit symbol substitution scores and subjective ratings. The effect on postural sway was markedly accentuated in the older volunteers, but the difference between groups in the effect on the other measures used did not achieve significance. The corresponding plasma total diazepam concentrations were lower in the older subjects beyond 0.5 h post dose and the concentrations of plasma desmethyldiazepam did not differ between the groups. Diazepam plasma protein binding was significantly reduced in the elderly subjects, but the plasma free (unbound) diazepam concentrations did not exceed those in the young group. There was poor correlation between the responses measured and the concentrations of either total diazepam, desmethyldiazepam or free diazepam. The results suggest the occurrence of a non-uniform effect of age on different aspects of benzodiazepine response, and that where an accentuated effect occurs the mechanisms are substantially pharmacodynamic.

Steady-state plasma desmethyldiazepam during long-term clorazepate use

The effect of antacid on steady-state plasma desmethyldiazepam (DMDZ) concentrations during long-term treatment with clorazepate dipotassium (CZP) was evaluated in 10 subjects. Each took 7.5 mg CZP nightly for 30 consecutive nights divided into three 10-day treatments given in random sequence as follows: (1) 7.5 mg CZP nightly with no antacid, (2) CZP nightly with 30 ml Maalox, and (3) CZP nightly with Maalox with an additional 30 ml Maalox three times daily. The overall mean steady-state DMDZ plasma level, measured during the last 3 days of each treatment condition, was 175 ng/ml. Within-day means ranged from 159 to 202 ng/ml and were not influenced by treatment condition, time, or trial sequence. DMDZ washout after termination of the 30-day trial was slow, proceeding with a half-life of 75 hr (range, 63 to 109 hr). Thus, Maalox does not alter steady-state DMDZ levels during long-term CZP therapy. Clinical Pharmacology and Therapeutics (1982) 31, 180–183; doi:10.1038/clpt.1982.28

Desmethyldiazepam kinetics in the elderly after oral prazepam.

Our subjects were 15 young (aged 22 to 42 yr) and 14 elderly (aged 62 to 85 yr) people who took single oral doses of 20 mg prazepam. Plasma desmethyldiazepam (DMDZ) concentrations were determined in venous blood samples drawn up to 9 days after the dose. Appearance in blood of DMDZ was slow, with peak plasma levels reached in an average of 10 to 20 hr. First-order DMDZ appearance was observed in only 17 subjects. Volume of distribution of total DMDZ (range, 1.33 to 6.30 l/kg) and of unbound DMDZ after correction for protein binding (range, 43 to 243 l/kg) was larger in women than in men of all ages, and in the elderly as opposed to the young. Elimination half-life (range, 29 to 224 hr) rose with age in men (r = 0.66, p < 0.01) but not in women (r = -0.02). Clearance of unbound DMDZ (range, 2.9 to 31.2 ml/min/kg) was greater in women than in men of all ages, and declined with age in men (r = -0.40) but not in women (r = -0.06). As in the case of diazepam, age can influence DMDZ kinetics, but changes in drug disposition with age may differ between sexes.

Monitoring clorazepate dipotassium as desmethyldiazepam in plasma by electron-capture gas--liquid chromatography.

Abstract We describe a procedure for determing clorazepate dipotassium as its decarboxylated, pharmacologically active metabolite, desmethyldiazepam, in 100 microL of plasma, with use of electron-capture gas--liquid chromatography and with methylnitrazepam as the internal standard. The procedure is a one-tube, one-step extraction without derivative formation and is accurate, reproducible, and rapid. The sensitivity limit is 20 micrograms/L. Within-run and between-run CV's (concentration, 3.5 mg/L) were 2.9 and 3.5%, respectively. Within-run CV's for 1.5 and 1.0 mg/L concentrations were 3.9 and 4.3%, respectively. For a 1.0 mg/kg per day dose of clorazepate dipotassium, the mean steady-state concentration of desmethyldiazepam in plasma was 1.037 mg/L.

Monitoring clorazepate dipotassium as desmethyldiazepam in plasma by electron-capture gas--liquid chromatography.

We describe a procedure for determing clorazepate dipotassium as its decarboxylated, pharmacologically active metabolite, desmethyldiazepam, in 100 microL of plasma, with use of electron-capture gas--liquid chromatography and with methylnitrazepam as the internal standard. The procedure is a one-tube, one-step extraction without derivative formation and is accurate, reproducible, and rapid. The sensitivity limit is 20 micrograms/L. Within-run and between-run CV's (concentration, 3.5 mg/L) were 2.9 and 3.5%, respectively. Within-run CV's for 1.5 and 1.0 mg/L concentrations were 3.9 and 4.3%, respectively. For a 1.0 mg/kg per day dose of clorazepate dipotassium, the mean steady-state concentration of desmethyldiazepam in plasma was 1.037 mg/L.

Determination of Desmethyldiazepam in Plasma by Electron-Capture GLC: Application to Pharmacokinetic Studies of Clorazepate

Plasma desmethyldiazepam concentrations were quantitated by a rapid and sensitive technique using electron-capture GLC. Following addition of diazepam as the internal standard, plasma is extracted at physiological pH into benzene–isoamyl alcohol. The extract is evaporated to dryness and reconstituted with toluene–isoamyl alcohol prior to chromatography. Both diazepam and desmethyldiazepam are quantitatively extracted. The variation of identical samples is 596, and the sensitivity is 5ng of desmethyldiazepam/ml of original sample. The method is applicable to Dharmacokinetic studies of clorazepate, a benzodiazepine derivative transformed to desmethyldiazepam prior to absorption.

INTERACTIONS BETWEEN DIAZEPAM AND PARACETAMOL

Summary A pharmacokinetic and metabolic study of diazepam has been made in four volunteers, two male and two female, with and without concurrent doses of paracetamol. Paracetamol did not produce significant changes in the profiles of diazepam and the metabolite desmethyldiazepam in plasma, although small alterations might not have been detected. However, the amount of diazepam and its metabolites excreted in the urine over 96 h was reduced by paracetamol, but statistically, for the group as a whole, the change was only marginally significant. In the two female subjects the effect was more pronounced and large enough to suggest that an interaction could occur in females if the two drugs were used together clinically.