Robert E. Weinfeld

Pharmacokinetics of diazepam following multiple-dose oral administration to healthy human subjects

Six healthy subjects between the ages of 21 and 31 years received diazepam tablets orally at a dose of 5 mg t.i.d. atO, 5, and 10hr on days 1–13. On day 14, the dose was 5 mg at 0 and 5 hr and 15 mg at 10 hr. Subsequently, the dose was 15 mg once daily on days 15–24. Numerous plasma samples were obtained during the multiple-dose regimen, and appropriate equations were fitted to all the multiple-dose data. Diazepam absorption was satisfactorily described by a first-order process, with disposition characterized by a linear two-compartment open model. The harmonic mean absorption half-life was 32 min, and the harmonic mean terminal exponential half-life was 57hr. The mean apparent oral total drug plasma clearance was 22.7ml/hr/kg. Steady-state plasma levels of the primary metabolite, desmethyldiazepam, were reached after 5–8 days of dosing. Steady-state diazepam plasma concentration-time profiles suggested that once daily administration of the total daily dose at bedtime might be a satisfactory dosing regimen.

Pharmacokinetics of flunitrazepam following single- and multiple-dose oral administration to healthy human subjects

Healthy human subjects received single and multiple oral doses of flunitrazepam. Absorption and disposition were first order and reproducible from administration to administration. The oral doses were virtually completely available to the liver, and elimination from the body occurred entirely via metabolism. Assuming the liver to be the sole eliminating organ, hepatic blood clearance and extraction ratio were approximately 0.235 liter/hr/kg and 0.154, respectively. Steady-state blood volume of distribution averaged 3.76 liters/kg in the single-dose studies. Terminal exponential half-lives from the single- and multiple-dose studies (different subjects) averaged 13.5 and 19.2 hr, respectively, these differences were not due to clearance changes but were entirely attributable to variations in volumes of distribution.

Blood levels and electroencephalographic effects of diazepam and bromazepam.

Blood levels and electroencephalographic (EEG) data were collected for 2 hr after single oral doses of bromazepam (9 mg), diazepam (10 mg), and placebo in 13 male adult volunteers. Both drugs caused an increase in beta activity (above 13 Hz) and a decrease in alpha activity (9 to 11 Hz) in the EEG. Blood levels of 100 nglml of diazepam or 50 ng Iml of bromazepam were associated with significant changes in EEG beta activity. Temporal changes in the EEG after administration of diazepam or bromazepam paralleled development of plasma levels of these drugs. Although a weakly significant correlation was found between measurable diazepam blood levels and amount of increased EEG beta activity, the relationship between measurable bromazepam blood levels and the degree of EEG changes was not significant. Quantitative EEG is a sensitive continuous response measure, useful in defining cerebral activity, response latency, and relative potency of psychoactive benzodiazepines.

Biopharmaceutical and clinical pharmacokinetic profile of bromazepam.

Bromazepam appears to be completely absorbed in man. The intact drug was eliminated from the blood with a mean half-life of 11.9 hr. Predictable steady-state blood levels are maintained on multiple daily dosing.

Clinical bioavailability evaluation of a controlled release formulation of diazepam

A controlled release formulation of diazepam was compared to equal daily doses of the trade tablet under single day and steadystate conditions. Virtually no differences were found in the mean steadystate concentrations of diazepam or its metabolite, N-desmethyldiazepam, when the subjects received the 5 mg trade tablet three times daily or the 15 mg controlled release formulation once daily. Similarly, there was no difference in mean diazepam or N-desmethyldiazepam plasma concentrations when single doses of the controlled release formulation were given to fed or fasted volunteers. These data indicate that the controlled release formulation produces plasma concentrations of diazepam and N-desmethyldiazepam comparable to those achieved with the same daily dose of the trade product given three times daily, suggesting that these regimens can be used interchangeably.

Changes in the oral absorption characteristics in man of dipotassium clorazepate at normal and elevated gastricpH

The in vivorate of biodegradation of dipotassium clorazepate to N-desmethyldiazepam in humans was shown to decrease with an increase in gastric pH. When gastric pH was maintained above 6 for 2 hr with sodium bicarbonate, the bioavailability of intact clorazepate, as determined by evaluating its conversion and absorption as N-desmethyldiazepam, was reduced from 5% to 75% when compared in the same subject with gastric pH less than 3. The corresponding N-desmethyldiazepam blood level maxima occurred later in time and were only 14–46% of the levels achieved from an acidic stomach. These findings indicate that the pH of the stomach can influence the absorption of dipotassium clorazepate.

Determination of clorazepate and its major metabolites in blood and urine by electron capture gas-liquid chromatography.

A sensitive and specific blood level method employing differential extraction was developed for the determination of clorazepate and its N-desmethyldiazepam metabolite by electron capture gas-liquid chromatography (GLC-ECD). The assay requires the initial extraction of N-desmethyldiazepam, the major metabolite, into benzene-methylene chloride (90:10) from the biological sample made alkaline with 0.1 N NaOH. The samples is then acidified with 2 N HCl to decarboxylate clorazepate to N-desmethyldiazepam, which is then extracted into benzene-methylene chloride (90:10) after adjusting the pH to 12.8 with NaOH. The two extracts are evaporated and the residues are dissolved in benzene which contains griseofulvin as the reference standard. These solutions are assayed by GLC-ECD. The overall recovery and sensitivity limit of the assay for clorazepate is 60+/-5% (S.D.) and 4.0 ng/ml blood, respectively, while that for N-desmethyldiazepam is 95+/-5% (S.D.) and 4.0 ng/ml blood, respectively. The urinary excretion of clorazepate was determined by the measurement of the levels of N-desmethyldiazepam and oxazepam, the major urinary metabolites of clorazepate, both prior to and after enzymatic deconjugation. These methods were applied to the measurement of clorazepate and its metabolites in blood and urine following a single 15-mg dose of clorazepate dipotassium.

Determination of trimethoprim in biological fluids by high-performance liquid chromatography

A rapid, sensitive, and specific high-performance liquid chromatographic assay was developed for the determination of trimethoprim in blood, plasma, and urine using normalphase (adsorption) chromatography on a microparticulate silica column and UV monitoring at 280 nm. Trimethoprim is selectively extracted from the biological sample matrix at alkaline pH with chloroform, providng nearly quantitative extraction (greater than 95%) and a sensitivity limit of 0.01 to 0.02 microgram/ml blood or plasma, without interference from sulfonamides.

Blood and salivary concentrations of sulfamethoxazole and trimethoprim in man

Saliva/blood and saliva/plasma concentration ratios were determined for sulfamethoxazole and trimethoprim following oral administration of cotrimoxazole to healthy human subjects. The mean experimentally determined saliva/plasma concentration ratios for sulfamethoxazole and trimethoprim were 0.0157 and 1.13, respectively. These values were shown to be in reasonable agreement with theoretical predictions. It was demonstrated that partitioning of drugs from saliva into the buccal must be considered in making theoretical predictions.

Rapid determination of diazepam and nordiazepam in plasma by electron capture gas—liquid chromatography : Application in clinical pharmacokinetic studies

A rapid method was developed for the determination of diazepam and nordiazepam (N-desmethyldiazepam) in human plasma using electron capture gas--liquid chromatography (GLC--ECE). The concentration of diazepam and nordiazepam is determined using 0.5 ml of plasma extracted with 1.0 ml of benzene containing 25 ng/ml of methylnitrazepam as the internal standard. The benzene extract is removed and an aliquot is subjected to automated GLC-ECD analysis. The method has a sensitivity limit of 5 ng diazepam and 10ng nordiazepam per milliliter of plasma. The method was used to determine the plasma levels in man following the first 5-mg diazepam dose, as well as during chronic oral administration of 5 mg diazepam three times daily and 15 mg diazepam once a day.