Gerald K. Shiu

An in vitro study of possible food-drug interactions of the controlled-release propranolol products

Abstract The pH-dissolution profiles of 4 controlled release (C.R.) propranolol products were investigated. Three of the products were pretreated with peanut oil prior to the dissolution testing to simulate drug administration with a fatty meal. The results were displayed in 3-dimensional graphs utilizing the topographical plotting technique of Skelly et al. The influence of pH on the in vitro drug release from the C.R. formulations was found to be less significant than the effect of lipid. A substantial decrease in dissolution rate that occurs with lipid pretreatment across the entire pH range suggests that lipid may have a significant effect on these C.R. drug products which are subject to a high first-pass effect.

THEOPHYLLINE-CONTROLLED RELEASE PREPARATIONS AND FATTY FOOD : AN IN VITRO STUDY USING THE ROTATING DIALYSIS CELL METHOD

The in vitro dissolution behavior of four controlled-release theophylline products was investigated utililzing the rotating dialysis cell method. The effects of pH, oil, and enzymes on the dissolution profiles were studied. The wide range of pH values and the content of oil and enzymes in the dissolution media in the dialysis cell, which functioned as an in vitro model, were simulated to mimic physiological changes due to food along the entire gastrointestinal tract. Treatment with oil affected the dissolution behavior of Uniphyl and especially Theo-Dur Sprinkle but had little or no effect on the dissolution profiles of Theo-Dur tablets and Theo-24 capsules. The in vitro observations of the oil effect were related to the food effect obtained from published in vivo studies. The rotating dialysis cell can be a useful tool in studying factors which may be responsible for dissolution-related food effects on the absorption of controlled-release products.

Study on the release of indomethacin from suppositories: in vitro-in vivo correlation

Abstract The in vitro dissolution kinetics of three different suppository formulations of indomethacin was studied using two different apparatuses, namely, a flow-through cell (Dissotest ®) and a dialysis rotating cell (Pharmatest ®). A comparison between both apparatuses was carried out and two types of dissolutions became apparent depending on whether the excipient used in the formulation was either hydrophilic or lipophilic. The distinction between dissolution profiles was more evident using the flow-through cell. From the in vivo curves parameters furnished by the manufacturers, in vitro/in vivo correlations were performed. A linear relationship was established between the in vitro results obtained and the in vivo percentages absorbed that were calculated according to the Wagner-Nelson method. Simulated blood concentration-time curves were generated from the in vitro released data and the pharmacokinetic parameters obtained. A good superimposition of the experimental plasma concentrations and the simulated curves was obtained with the flow-through cell and the hydrophilic suppository dosage form whereas the simulation with the lipophilic suppository gave imperfect results irrespective of the apparatus used.

Reduced Bioavailability of Moisture‐Exposed Carbamazepine Resulting in Status Epilepticus

A 28‐year‐old man with seizures well controlled with carbamazepine (CBZ) and valproate (VPA) developed generalized convulsive status epilepticus three days after his CBZ tablets became wet during a rainstorm while he was camping out. He continued the CBZ but avoided ingesting obviously disintegrating tablets. The VPA was not exposed to excessive moisture. Previous random CBZ blood levels had been in the range of 9–13 μg/ml; at the time of admission to the emergency room the level had decreased to 3.8 μg/ml. The VPA level did not change significantly from baseline. The moistureexposed CBZ tablets were of expected weight but were swollen and enlarged. Analysis of these tablets by USP paddle method 2 demonstrated a mean dissolution of 16% at 60 min as compared with >80% for fresh CBZ tablets. After final dissolution of the moisture‐exposed CBZ tablets, normal quantities of active drug were noted. We propose that poor dissolution of moisture‐exposed CBZ tablets results in reduced bioavailability. We urge caution in the packaging and storage of CBZ to avoid exposure to moisture.

The Beagle Dog as an Animal Model for a Bioavailability Study of Controlled-Release Theophylline Under the Influence of Food

Beagle dogs were evaluated as an animal model to study the effect of food on the bioavailability of two commercially available oral controlled-release theophylline products. The products were administered with and without food in single doses, and the bioavailability parameters were compared with those following an i.v. aminophylline dose. The total plasma theophylline clearance in dogs following an i.v. dose was 0.128 liter/hr/kg and the volume of distribution was 0.8 liter/kg using a one-compartment model. The absolute bioavailabilities of these two products under fasting conditions were 31 and 48%, respectively. The food increased the bioavailability of one product and decreased the bioavailability of the other. The overall trends in relative bioavailability of these two products with and without food appeared to be similar to those reported in humans.

The Effect of Food on the Absorption of Controlled-Release Theophylline in Mini-Swine

The effect of differing fat contents of food on the bioavailability of theophylline following a 400-mg single dose of Theo-24 was studied in mini-swine. The pharmacokinetics of theophylline, following the intravenous administration of aminophylline equivalent to 5 mg/kg as a single dose, were also studied in the same animals. The terminal plasma half-life of theophylline following an i.v. dose was found to be approximately 24 hr. The volume of distribution, Vdext, and clearance following the i.v. dose were approximately 0.7 liter/kg and 0.023 liter/hr/kg, respectively. The terminal half-life of theophylline following the administration of theophylline capsules under fasting conditions was 21 hr. The average bioavailability under fasting conditions was approximately 80% compared to the i.v. dose. Food appeared to have decreased the rate of absorption but no significant effect on the extent of absorption.

Capillary gas chromatographic (GC) analysis of nitroglycerin and its denitration products in plasma.

A convenient, specific, and sensitive capillary gas chromatographic (GC) assay for analyzing nanogram concentrations of nitroglycerin and its dinitro- and mononitrometabolites in plasma has been developed. Using a bonded-phase (DB-1) 30-m, 1-µm-thick film capillary column and a 1-m, 5-µm-thick film precolumn, separation of nitroglycerin and all four partially nitrated metabolites was achieved in less than 15 min. On-column injection, electron capture detection, and isothermal operation at 100°C yielded a linear extraction curve over a 300-ng/ml range without any need to concentrate sample extracts. Using methyl t-butyl ether as extraction solvent and o-chloronitrobenzene as internal standard, recoveries from plasma spiked at levels greater than 10 ng/ml approximated 35% for the 1-monometabolite, 40% for the 2-monometabolite, and greater than 90% for all others. The method was employed in a pharmacokinetic study of nitroglycerin administered intravenously to beagle dogs. Plasma samples were collected at various time points and analyzed.