Temazepam In Plasma Research Articles

Quantitative analysis of temazepam in plasma by capillary gas chromatography: Application to pharmacokinetic studies in rats

A sensitive method was developed for the determination of temazepam in plasma using capillary gas chromatography. After the extraction into dichloromethane-pentane (1∶1), temazepam was quantitated as its O-trimethylsilyl derivative on a capillary column with a63Ni electron capture detector using prazepam as internal standard. The detector response was found to be linear in the concentration range 0.031 to 8 μg mL−1. The detection limit was about 3.5 ng mL−1. The intraday and inter-day coefficients of variation were below 9%. The method was used to determine the pharmacokinetic profile of temazepam in rats after intravenous administration.

The relationship between clinical effect and concentrations of temazepam in plasma and cerebrospinal fluid.

The clinical pharmacodynamics of temazepam were investigated in patients who received spinal anaesthesia. Total plasma and cerebrospinal fluid temazepam concentrations were measured and correlated with the clinical effects. Sedation was measured by three separate methods. None, including an aggregated score of all three measures, was correlated closely with either the plasma or the cerebrospinal fluid levels (p = 0.86 and 0.12 respectively). Anxiety was measured before and after premedication. The two scores were correlated but the change in anxiety after premedication did not correlate with either the plasma or the cerebrospinal fluid concentrations (p = 0.11 and 0.45 respectively). Short-term memory was measured before and after premedication. The decline in short-term memory ability was moderately well correlated with both the plasma and the cerebrospinal fluid levels (p = 0.0005 and 0.013 respectively). With temazepam, the variation in sedative and anxiolytic effects between subjects is explained not by differences in pharmacokinetics but rather by differences in the pharmacodynamic response. Because sedative and anxiolytic effects are poorly correlated, but the amnesic effect is well correlated with temazepam concentrations, different sites of action for these effects are suggested.

Oxidative versus conjugative biotransformation of temazepam

Twenty-four healthy volunteers, aged 21-59 years, received single 30 mg oral doses of the benzodiazepine hypnotic temazepam. Levels of intact temazepam were determined in multiple plasma samples drawn during 48 h after dosage. Intact temazepam, its direct glucuronide conjugate, and the conjugate of its demethylated (oxidized) metabolite oxazepam were measured in two consecutive 24-h urine collections. Mean kinetic variables for temazepam in plasma were: peak plasma level (Cmax), 873 ng ml-1; time of peak, 1.36 h after dosage; volume of distribution, 0.961 kg-1; elimination half-life 9.9 h; clearance, 1.16 ml min-1 kg-1. Volume of distribution increased significantly with body weight (r = 0.67, p less than 0.001), and Cmax decreased with weight (r = -0.58, p less than 0.01). Only 0.2 per cent of the dose was excreted as intact temazepam, and negligible amounts as intact oxazepam. However, 39 per cent of the dose was recovered as temazepam glucuronide, and oxazepam glucuronide accounted for another 4.7 per cent of the dose. The remainder was not accounted for. Thus, a significant fraction of temazepam clearance occurs by direct glucuronide conjugation, with the conjugate temazepam glucuronide excreted in urine. A much smaller fraction undergoes parallel oxidation to form oxazepam, which is subsequently conjugated to oxazepam glucuronide and excreted in urine.

Plasma and cerebrospinal fluid concentrations of temazepam following oral drug administration

Thirteen male patients were administered 20 mg of temazepam orally 1 to 2 h prior to undergoing spinal anaesthesia for a urological procedure. Samples of blood and CSF were drawn just before insertion of the spinal and the concentration of drug estimated in these two media. The results obtained indicated that a highly significant correlation existed between the unbound concentration of temazepam in plasma and the concentration of drug present in CSF. Temazepam appeared to be an effective light pre-medicant in all of the subjects studied.

A Methodological Comparison of Two Formulations of Temazepam in Pharmacokinetic and Pharmacodynamic Aspects

In a double-blind and cross-over study 12 healthy subjects took temazepam 20 mg in two different formulations (soft gelatine capsule or uncoated tablet) and matched placebo at one-week intervals. Plasma temazepam concentrations at 0.5, 1, 2, 3, 8, 12 and 24 hours after treatment were analyzed by gas chromatography. Psychomotor performance was measured objectively (digit symbol substitution, letter cancellation, Maddox wing test) and subjectively (visual analogue scales) before the drug intake and 1, 2 and 3 hours later and the plasma benzodiazepine concentrations were analyzed also by radioreceptor bioassay. The two different formulations were compared in pharmacokinetic and pharmacodynamic terms, and the gas chromatographic and radioreceptor assays were compared. The soft gelatine capsule produced higher peak plasma concentrations than the uncoated tablet. The computed AUCs and elimination half-lives proved to be similar after either formulation. A satisfactory correlation between the bioassayed benzodiazepine concentrations and chemically assayed temazepam was shown. In pharmacodynamic terms the results suggest a shorter and somewhat smaller subjective response for the capsule than for the tablet form.

COMPARISON OF SEDATION WITH TEMAZEPAM BY MOUTH AND DIAZEMULS I.V. FOR DENTAL SURGERY: Variability in Absorption may Influence Clinical Effect

Temazepam elixir 30 mg by mouth was compared with i.v. Diazemuls titrated to a maximum dose of 20 mg in a double-blind study of 50 patients undergoing elective minor oral surgery. The treatments produced a similar reduction in anxiety score and similar degrees of patient relaxation and co-operation. The diazepam group had greater amnesia during surgery, but also showed significant slowing of reaction time at the time of discharge. Patients given temazepam elixir showed wide variations in plasma concentrations. Patients with low plasma temazepam concentrations at the time of surgery showed no significant reduction in anxiety scores.

Determination of temazepam in plasma and urine by high-performance liquid chromatography using disposable solid-phase extraction columns

Temazepam (Fig. 1) is a 1 ,Cbenzodiazepine used clinically as an hypnotic agent [l]. Its metabolism and pharmacokinetics have been described previously [2-31. Assay methods for temazepam have been described using polarography [4-51, gas chromatography (6-81 and high-performance liquid chromatography (HPLC) [9]. All of the methods described utilize organic extraction for sample preparation prior to analysis. This report describes an HPLC method using inexpensive disposable solid-phase extraction columns which represents a significant improvement over previous techniques in speed of sample preparation and analysis time.

Pharmacodynamic evaluation of the benzodiazepine-oral contraceptive interaction.

The sedative, psychomotor, and memory effects of single oral doses of alprazolam (ALP), lorazepam (LOR), temazepam (TMP), and triazolam (TRZ) were evaluated in women taking oral contraceptives (OCs) and a comparable group of control women. Nine women taking OCs and 11 control women took doses of 1 mg ALP and 2 mg LOR and 10 OC users and 10 control women took 30 mg TMP and 0.5 mg TRZ on two occasions separated by 28 days. Minimal psychomotor impairment was noted after TMP. ALP, LOR, and TRZ produced greater performance impairment in the OC users. Correcting the maximum observed performance decrement for plasma concentration did not account for the differences between OC users and controls. After TMP, there was less sedation during the first 2 hours in OC users, who also had higher plasma TMP clearance. There were no differences in sedation between OC users and controls after ALP, LOR, and TRZ; however, there was less than 50% power to detect a 30% difference. Amnestic effects in OC users and controls did not differ after any of the four drugs. The observed patterns of anterograde amnesia were different, with the earliest and most pronounced recognition failure after TRZ (50% at 1.5 hours), while the LOR effect increased to a maximum (30%) 4 hours after dosing. Our data suggest that differences in benzodiazepine pharmacokinetics between OC users and control women do not account for observed differences in psychomotor impairment. Women taking OCs are more sensitive to the psychomotor effects of single oral doses of benzodiazepines.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of end-stage renal disease and aluminum hydroxide on temazepam kinetics

The kinetics of temazepam, 30 mg, were evaluated in 11 patients with end-stage renal disease. Age ranged from 18 to 65 years. On two occasions separated by 1 week, single oral 30 mg doses of temazepam were given once with water (TM) and once with 3600 mg aluminum hydroxide gel (TM + AHG). There were no significant differences in the maximum plasma concentration, the time to reach maximum concentration, or elimination rates between TM and TM + AHG dosing. In approximately half the subjects there were secondary temazepam peak concentrations. In the remaining subjects, temazepam elimination was biphasic, with the terminal t1/2 ranging from 11 to 77 hours. There was a lag time before absorption in all subjects. The percent free temazepam in plasma from dialysis subjects ranged from 4.4% to 8.8% (mean = 5.9%). Compared with literature reports of subjects with normal renal function, the maximum plasma concentration was lower and the percent free temazepam was higher in dialysis subjects. When sedation score was plotted against plasma temazepam concentration, there was clockwise hysteresis consistent with tolerance or adaptation to effects of the drug. Thus aluminum hydroxide gel does not affect temazepam absorption. The clinical significance of the low plasma concentrations and high free temazepam fraction in dialysis subjects is uncertain.

Noninteraction of Temazepam and Cimetidine

The possible kinetic interaction of the hypnotic temazepam and the H2-receptor antagonist cimetidine was evaluated. Nine healthy male and female volunteers received a 30-mg oral dose of temazepam on two occasions in random sequence, separated by at least 1 week. On one occasion, temazepam was given in the otherwise drug-free state; on the other, temazepam was given with concurrent administration of cimetidine, 300mg every 6h. Mean pharmacokinetic parameters for temazepam in control versus cimetidine trials were: peak plasma concentration, 560 versus 498 ng/mL; time of peak concentration, 2.0 versus 2.1 h after the dose; volume of distribution, 1.30 versus 1.39 L/kg; elimination half-life, 9.9 versus 11.4h; total clearance, 1.59 versus 1.60 mL/min/kg; free fraction of temazepam in plasma, 4.1 versus 3.8% unbound. Cimetidine has been shown to reduce the metabolic clearance of the benzodiazepines that are biotransformed by oxidative mechanisms. Temazepam, transformed by conjugation, appears unaffected by the coadministration of cimetidine.

Determination of nitrazepam and temazepam in plasma by high-performance liquid chromatography.

A rapid and simple high-performance liquid chromatographic analysis of nitrazepam in plasma with temazepam as an internal standard is described here. Alternatively, this assay method can also be used to determine temazepam plasma concentrations with nitrazepam as the internal standard. Chloroform was used as an organic solvent for the extraction process. The percentage recoveries of nitrazepam and temazepam were 79% and 85%, respectively. The coefficient of variation of the within-day precision of the assay procedure at a concentration equal to 50 ng/ml of nitrazepam was 2.4% (n = 5), and that for day-to-day precision at the same concentration was 4.7% (n = 5). Calibration curves for nitrazepam and temazepam were linear over their therapeutic ranges. Pharmacokinetic parameters obtained with this method after a single oral dose of 5 mg of nitrazepam in five normal subjects were comparable to results obtained in previous studies.

Effect of age and gender on disposition of temazepam

Thirty-two male and female volunteers, 24-84 years of age, ingested single 30-mg doses of temazepam, a 3-hydroxy-1, 4-benzodi-azepine 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 < 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 < 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 1.7-3.4%). 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 < 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 < p < 0.1), and it tended to decline with age in both sexes (r = −0.44 and −0.43, respectively, p = 0.1).