W. J. Brown

Plasma Level Studies of Penbutolol After Oral Dose in Man

Plasma levels of penbutolol (HOE 893d) were determined in eight healthy adult male subjects after oral administration of 50-mg capsules. Fast absorpiton of the drug from the gastrointestinal tract was indicated by the rapid increase in plasma levels during the absorption phase, with a peak time at about 1 hour after dosing in all subjects. After the peak level, plasma concentrations declined biexponentially, with an average half-life of 2.5 and 27 hours for the fast and slow disposition phases, respectively. These values were in good agreement with data previously found for this drug. Cumulative excretion of intact drug in the urine of the eight subjects during 72 hours after dosing was less than 4 per cent, except for one subject who excreted 9.82 per cent of the dose. Large individual variations were found for area under the plasma level curves, disposition rates, and amounts of intact drug excreted in the urine. Significant pharmacologic effects were noted in all eight subjects at the 50-mg dose level, and mild side effects were evident in one half of these subjects. The average drop in blood pressure and pulse rate for all subjects was 26/18 mm Hg and 19 beats per minute, respectively.

Plasma levels of clobazam after 10-, 20-, and 40-mg tablet doses in healthy subjects.

It is evident that substantial intersubject and intrasubject varition in the bioavailability of clobazam exists following ingestion of 10, 20 and 40 mg doses in these 12 volunteers. Peak concentrations and area under the plasma level-time curve were directly proportional to the dose of clobazam and the mean plasma half-life of clobazam was about 18 hours regardless of dose administered. The t1/2 value was less than that previously reported, as the current results allow differentiation of parent drug from metabolites. This 18 hr t1/2 compares favorably with the half-life of other benzodiazepines.

Plasma Levels of Clobazam After Three Oral Dosage Forms in Healthy Subjects

As can be seen from the tables, the terminal half-life of clobazam is about 50 hours, and from a solid dosage form the peak plasma level occurs approximately 1.5 hours after ingestion. Thus, there is a significant, yet relatively short, dosage form delay effect when the solid dosage forms are compared to the rapidly available solution of the drug. However, based on the areas under the curve, comparison of the solid dosage forms with the solution indicates that the fraction of clobazam absorbed is 1. Pupil diameter measurement at 2, 4, and 6 hours after ingestion of clobazam correlated well with the plasma levels at these times. Pupils were constricted to the highest degree at 2 hours and approached the initial pupillary diameter at the 6-hour measurement.

Stabilized venous distensibility of normotensive and hypertensive humans on high and low sodium intake.

Venous responses to stabilized orthostasis (45 degrees head-up tilt) were studied in seven normotensive subjects and eight hypertensive patients, when on high and low dietary sodium intake. Exchangeable sodium and blood volumes were determined to permit correlation with any significant changes in venous behavior. The intent of this study was to detect and analyze any diet-induced changes in responses of forearm veins to prolonged orthostasis. The pharmacological effects of sodium depletion by medication and diet on arteries and veins of hypertensives are discussed. The results of this study indicate that dietary sodium depletion did not have adverse effects on the ability to maintain stabilized venous tone during orthostasis. These results support recommendations that moderate dietary sodium restriction be included as part of antihypertensive regimens.

An in vivo single- and multiple-dose study of several marketed brands of conventional and controlled-release theophylline.

In a single-dose study, 18 healthy adult males consumed each of six dosage forms of theophylline. A conventional-release tablet, a syrup, and four competing brands of controlled-release theophylline were studied. Serial serum samples were obtained and analyzed via high pressure liquid chromatography (HPLC). After achieving steady state, 15 healthy adult males consumed each of five dosage forms of theophylline in a multiple-dose study. Serial blood samples were obtained between 0 and 72 hours and subjected to analysis with HPLC. The results indicated that the controlled-release products were not bioequivalent, although they achieved longer time-to-peak values than did the immediate-release syrup and the conventional-release tablet. A single sustained-release product was uniquely different on most pharmacokinetic parameters when compared with the remaining three controlled-release products. In general, the dosage form variation exceeded the individual subject variation on the single-dose study, but the opposite was true for the multiple-dose study.