I.L. Honigberg

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.

Normal phase LC-MS determination of retinoic acid degradation products.

The degradation products formed when 13-cis retinoic acid (13-cis RA) and all-trans RA were exposed to fluorescent light and air were investigated. These retinoids are known to undergo Z-E isomerization (due to the existence of four unsaturated double bonds) and oxidation when exposed to light and air. Analysis by LC was carried out on a 25 cm x 4.6 mm Zorbax Rx-SIL (5 microns) with a mobile phase (1.4 ml min-1) of heptane-THF-acetic acid (96.5:3.5:0.015) and an in-line UV (365 nm) detector. The LC eluate was coupled through a Vestec universal interface to a Finnigan 4023 mass spectrometer. EI-mass spectra were obtained at 77 eV from m/z 200 to 350 with multiplier voltage of 1200 V. Solid samples of 13-cis RA and all-trans RA exposed to light and air and also solutions of these retinoids in the mobile phase exposed to the same conditions were used for the analysis. Tentative identities of the degradation products from the mass spectra suggest the isomerization of the retinoids (Z-E isomerism) and the formation of the 5,6-epoxides of these isomers. Identities of the 5,6-epoxides were confirmed with chromatographic and mass spectral data from synthetic samples of the epoxides. Isomerization occurred more readily in solution than in the solid form and the 13-cis RA isomer oxidized more readily than the all-trans isomer.

Separation of 13-cis and all-trans retinoic acid and their photodegradation products using capillary zone electrophoresis and micellar electrokinetic chromatography (MEC)☆

Two retinoic acid isomers; 13-cis retinoic acid and all-trans retinoic acid and their photodegradation products were resolved with capillary electrophoresis (CE) (UV detector, 345 nm) using three different mobile phases: method 1--an acetonitrile modified borate buffer (pH 8.5); method 2--borate buffer (pH 8.5) modified with acetonitrile and alpha-cyclodextrin; and method 3--borate buffer (pH 8.5) modified with SDS (MEC). Concentration of acetonitrile in the buffer was varied from 10 to 50% in method 1 and resolutions of 0-1.9 were obtained for the two retinoic acid isomers. Similarly in method 2, concentration of alpha-cyclodextrin in the buffer (with 10% acetonitrile) was varied from 0 to 40 mM, giving resolutions of 0-3.8. In method 3, concentration of SDS in the buffer was varied from 5 to 60 mM resulting in resolutions of 1.3-4.1. Optimum separation conditions for the three methods were applied to the separation of photodegradation products of the two retinoids after exposure to fluorescent light for 36 h. A buffer modified with 45% acetonitrile and the same buffer modified with 10 mM SDS gave incompletely resolved electropherograms with a 72 cm x 50 microns capillary (50 cm to the detector). A buffer containing 20 mM alpha-cyclodextrin 10% acetonitrile gave completely resolved peaks for each isomer. The buffer containing 10 mM SDS gave completely resolved peaks for the photodegradation products when a 122 cm x 50 microns capillary (100 cm to detector) was used.

A comparison of solid-phase extraction techniques for assay of drugs in aqueous and human plasma samples

Abstract Six commercially available solid adsorbent materials were evaluated for their applicability as effective tools for extraction of drugs from aqueous and human plasma samples. Ten model compounds were selected as representative of the acidic, basic, amphoteric, hydrophobic, and hydrophilic drug classes. Percent recovery and precision data for each model drug on each solid adsorbent material were calculated using spiked water and/or plasma samples. Octadecylsilane materials were the best overall choice for extraction of the different chemical classes of drugs from water and plasma samples, giving both highest recovery and best reproducibility data for a majority of the drugs studied. It was also determined that good extractability for basic drugs could be obtained using either XAD-2, Clin-eht® or cyanopropyl columns. In addition, XAD-2 gave good recoveries of amphoteric compounds and Clin-elut® was good for hydrophobic drugs.

LCEC Detector with Graphite-Teflon Electode

Abstract A compression molded graphite-Teflon electrode is evaluated as a detector for the electrochemical detection of phenolic compounds, separated by reverse-phase high-performance liquid chromatography. Detection limits for these phenolic compounds range from 0.5–1 ng. Repetitive injections yield peak heights with RSDs less than 1%. Passivation of electrode surface by phenols is discussed. In addition, construction of a flow cell to be used in conjunction with graphite-Teflon electrode is also described.

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.

Electrochemical detection of retinoids using normal phase HPLC

Abstract Non-aqueous electrochemical (EC) detection of 13-cis-retinoic acid, all-trans retinoic, acitretin and vitamin A palmitate in non-aqueous solvents are reported. Non-aqueous (EC) detection allows for normal-phase chromato-graphy of these compounds prior to detection. The normal phase system used a mobile phase of HEX/THF/AcOH for the separation of all four compounds. The stationary phase was either silica or PVA-sil. The lipophilic salts, t-butylammoniumtetrafluoroborate or t-butyl-ammoniumhexafluorophosphate necessary for EC detection were added post-column. The limit of detection (LOD) for EC detection of these compounds is approximately 1 ng on column compared with an LOD by UV absorption of 2 ng on column. The linear detection for these compounds with the EC detector was about two orders of magnitude.

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.