Gas chromatographic analysis of alprazolam in plasma: replicability, stability and specificity.
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Alprazolam↗
Biomedical subjects
A Locniskar
Publications and source records attributed to A Locniskar.
Pharmacokinetic and electroencephalographic study of intravenous diazepam, midazolam, and placebo.
Eleven healthy volunteers received a single intravenous dose of diazepam (0.15 mg/kg), midazolam (0.1 mg/kg), and placebo by 1-minute infusion in a double-blind, three-way crossover study. Plasma concentrations were measured during 24 hours after dosage, and the electroencephalographic (EEG) power spectrum was simultaneously computed by fast-Fourier transform to determine the percentage of total EEG amplitude occurring in the 13 to 30 Hz range. Both diazepam and midazolam had large volumes of distribution (1.2 and 2.3 L/kg, respectively), but diazepam's half-life was considerably longer (33 versus 2.8 hours) and its metabolic clearance lower (0.5 versus 11.0 ml/min kg) than those of midazolam. EEG changes were maximal at the end of the diazepam infusion and 5 to 10 minutes after midazolam infusion. Percent 13 to 30 Hz activity remained significantly above baseline until 5 hours for diazepam but only until 2 hours for midazolam. For both drugs, EEG effects were indistinguishable from baseline by 6 to 8 hours, suggesting that distribution contributes importantly to terminating pharmacodynamic action. The relationship of EEG change to plasma drug concentration indicated an apparent EC50 value of 269 ng/ml for diazepam as opposed to 35 ng/ml for midazolam. However, Emax values were similar for both drugs (+19.4% and +21.3%, respectively).
Adult↗
A large-sample study of diazepam pharmacokinetics.
Healthy male volunteers (n = 48) aged 18-44 years received a single 10-mg oral dose of diazepam. Plasma diazepam and desmethyldiazepam concentrations were measured at multiple points during the next 11 days. The distribution of peak plasma concentration (mean, 406 ng/ml) was not skewed and did not differ significantly from normal (Guassian). However, the distributions of elimination half-life (44.2 h), elimination rate constant (0.0219/h), clearance (26.6 ml/min), and volume of distribution (83 L) all were significantly skewed and deviated significantly fron normal. After logarithmic transformation, the distributions of elimination rate constant, elimination half-life, and volume of distribution were consistent with normal; however, this was not the case for time of peak plasma concentration. Thus, the pharmacokinetic characteristics of oral diazepam are highly variable even in a relatively homogeneous population. Parametric statistical testing procedures and pharmacokinetic forecasting schemes may be improved by more precise delineation of the underlying distributions for pharmacokinetic variables.
Adolescent↗
Lorazepam kinetics in the elderly.
Lorazepam is a 3-hydroxy-1,4-benzodiazepine derivative biotransformed by glucuronide conjugation, followed by urinary excretion of the glucuronide metabolite. The kinetic properties of single 1.5- to 3.0-mg doses of intravenous lorazepam were assessed in 15 healthy elderly subjects, 60 to 84 yr of age, and in 15 healthy young subjects, 19 to 38 yr of age. Volumes of distribution for lorazepam in the elderly group (mean, 0.99 1/kg), were slightly but significantly smaller than in the young group (1.11 1/kg), suggesting less extensive drug distribution in the elderly. Values of elimination half-life (t1/2beta) in the elderly (15.9 hr) did not differ significantly from those in the young group (14.1 hr), but total clearance in the elderly (0.77 ml/min/kg) was 22% less (p less than 0.05) than in the young subjects (0.99 ml/min/kg). Age differences in lorazepam clearance were partly explained by more frequent cigarette smoking in the young subjects. Gender had no apparent relationship to kinetics. The rate and completeness of absorption of intramuscular (IM) and oral loraxepam was assessed in 10 of the elderly subjects. Deltoid IM injection and oral administration of tablets in the fasting state led to rapid absorption of lorazepam into the systemic circulation. Peak plasma lorazepam concentrations were always reached within 2.5 hr, and values of absorption half-life (t1/2a) did not exceed 45 min. Absorption of IM and oral lorazepam was 80% to 100% complete. Thus, the aging process is associated with small changes in the kinetics of lorazepam. IM and oral administration of lorazepam in elderly persons, as in the case of young individuals, leads to rapid and nearly complete absorption into the systemic circulation.
Absorption↗
Spectrophotometric assay of antipyrine in plasma: a reevaluation.
The linearity, sensitivity, and replicability of the spectrophotometric antipyrine assay were reevaluated. Standard curves are always linear through concentrations of at least 50 microgram/ml, whether prepared in water, dilute acid, or plasma. Sensitivity limits are 1 to 2 microgram of antipyrine per ml of plasma in healthy individuals. Within-day coefficients of variation for identical samples ranged from 12.3% at 2 microgram/ml to 1.2% at 50 microgram/ml. Identical samples assayed two years apart deviated by a mean of 3.8%, indicating high between-day replicability as well as stability during prolonged storage at -20 degrees C. Thus the spectrophotometric assay for antipyrine is suitable for most clinical pharmacokinetic studies.
Antipyrine↗
Bioinequivalence of a generic brand of diazepam.
Twenty-six healthy male volunteers received a single 10 mg dose of diazepam on two occasions in a crossover bioequivalence study comparing the reference product (Valium) and a generic formulation (NeoCalme). Concentrations of diazepam and its metabolite, desmethyldiazepam, were determined during 264h after each dose. Peak plasma diazepam concentrations were significantly lower for NeoCalme vs Valium (247 vs 394 ng ml-1, p less than 0.001) and reached significantly later after the dose (1.62 vs 0.98 h, p less than 0.001). Total area under the plasma concentration curve (AUC) was also significantly lower for NeoCalme (6614 vs 7552 ng ml-1 x h, p less than 0.001), although AUC ratios for NeoCalme divided by Valium satisfied the '75-75' guidelines. Findings for desmethyldiazepam were similar. Thus, diazepam absorption from the generic brand of diazepam is significantly slower than from Valium, which in turn could lead to therapeutic inequivalence.
Adult↗
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.
Adult↗