J.J. Vallner

Pharmacokinetics and Bioavailability of Hydromorphone Following Intravenous and Oral Administration to Human Subjects

Abstract: In a relatively small pilot study, the half‐life of elimination of hydromorphone in six subjects was 2.64 ± 0.88 hours and the drug had a high volume of distribution, 1.22 1./kg. In addition, the drug was rapidly but incompletely absorbed after oral administration. An equation to predict the plasma concentration of hydromorphone on oral administration was developed from the data of these six subjects.

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.

A proposed general protocol for testing bioequivalence of controlled-release drug products

Abstract This paper proposes methods to test whether marketed or newly developed controlled-release drug products are functioning in the manner indicated by the formulation and product literature. Typical controlled-release preparations are supposed to release part of the dose immediately, the amount should be essentially consistent with a conventional release single-dose product, and the rest of the dose at a constant (zero-order) or nearly constant rate. These release patterns can be effectively evaluated by calculation of a controlled-release effectiveness (CRE) parameter and an absorption rate effectiveness (ARE) parameter described herein.

Quantitation of cefazolin sodium in plasma and tissues by high-performance liquid chromatography

Abstract A sensitive and reproducible HPLC method for the determination of cefazolin sodium in plasma and tissues of albino rats was developed. The assay technique utilizes a simple methanol extraction of the antibiotic and sulfamethoxazole or succinyl sulfathiazole as the internal standard. The proteins in plasma or tissue homogenates were precipitated by the addition of concentrated solution of trichloroacetic acid. Separation of the drug was performed on a μBondapak C 18 column using a 0.1 M sodium acetate buffer (pH 3.85): acetonitrile (89:11) mobile phase and the eluent was monitored at 254 nm. The limits of detection were 0.1 μg/ml of plasma and 1 μg/g tissue, and the linearity ranges were 0.1–200 μg/ml of plasma and 1–40 μg/g tissue. An excellent linear correlation was observed between the peak height ratios and the cefazolin concentration ( r 2 = not less than 0.999). Minimum and maximum coefficient of variation were 2.54% and 3.12%, respectively, for the plasma and 2.17% to 3.51% and 0.82% to 3.06% for tissues at the concentration levels of 2 μg/ml (g) and 20 μg/ml (g), respectively. The method has been used to study cefazolin physiological pharmacokinetics in more than 80 rats and has been proven to be reproducible and sensitive.

An ultraviolet difference spectrophotometric method for determination of drug-binding parameters

Abstract Ultraviolet (u.v.) difference spectrophotometry is a direct technique to probe ligand/ macromolecule interactions. The difference technique is very sensitive to the interactions that occur and can be used with ligands of limited solubility. A method for reducing the binding data gathered from the u.v. difference technique is now described. Data from the literature as well as obtained in these laboratories were reduced by using a plot of change in absorbance difference versus added perturbant concentration. Deviation from initial linearity enables the concentration of free and bound ligand to be determined and hence the binding parameters can be calculated by standard techniques. Literature and laboratory binding data are calculated for phenylbutazone, oxyphenbutazone, sulindac, diclofenac, ethacrynic acid, and sulfadimethioxine.