T.E. Needham

RESEARCH ARTICLESSolubility of Amino Acids in Pure Solvent Systems

The effects of various solvents and pH on the solubilities of glycine, L-alanine, L-valine, L-phenylalanine, and DL-amino-octanoic acid were studied in a series of pure aqueous and alcoholic solutions. The aqueous solubility was found to be inversely proportional to the size of the nonpolar portion of the molecule. A low nonaqueous solubility seemed to be due to a dominance of the amino acid by the charged L-amino carboxylic acid portion of the molecule. In aqueous and alcoholic solutions, an isoelectric band of minimum solubility was formed. A distinct increase in solubility proportional to the addition of acid or base was seen as the pH exceeded the limits of the isoelectric band. In the alcoholic solvent systems studied, the addition of either acid or base produced a greater divergence from the isoelectric pH than would be seen in a pure aqueous system.

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.