Comparative bioavailability and steady state fluctuations of Tegretol commercial and carbamazepine OROS tablets in adult and pediatric epileptic patients.

The comparative bioavailability and steady state fluctuations resulting from the administration of Tegretol 200 mg commercial tablets and carbamazepine OROS controlled delivery tablets were investigated in 22 adult and 12 pediatric epileptic patients. Tegretol commercial tablets were dosed according to previously established clinical regimens of 400 to 2000 mg daily doses divided into four equal or unequal intervals. Carbamazepine OROS was dosed every 12 h at the same corresponding daily dose. Comparisons of the pharmacokinetic parameters AUC, Cmax, Cmin, and tmax at steady state for the two dosage forms demonstrated definitively the bioequivalence of carbamazepine OROS with Tegretol commercial tablet over a 24-h treatment interval.

Effect of food and relative bioavailability following single doses of diclofenac 150 mg hydrogel bead (HGB) capsules in healthy humans.

The effect of food on the bioavailability of diclofenac from a 150 mg diclofenac hydrogel bead (HGB) capsule was evaluated in 12 healthy male subjects in a fed and fasted state. Additionally, the fasting bioavailability of diclofenac from a 150 mg diclofenac HGB capsule relative to diclofenac sodium in buffered aqueous solution was evaluated in these same 12 subjects. The study was designed as an open-label, randomized, single-dose, 3 x 3 Latin-square crossover trial balanced for residual effects. A 2-week washout period was maintained between treatments. Blood samples were collected at frequent intervals over a 24-h period with plasma being separated and analyzed for diclofenac using a validated HPLC method. The administration of the 150 mg diclofenac HGB capsule dose within 30 min following a standardized breakfast minimally affected the bioavailability of diclofenac relative to administration under fasted conditions (7 per cent decrease in AUC(0-24), p greater than 0.05). There was, however, a 38 per cent decrease (p less than 0.05) in the Cmax and a three-fold increase (p less than 0.05) in Tmax for the fed HGB capsule administration. Under fasted conditions, significant differences in mean pharmacokinetic parameters were found between the 150 mg diclofenac HGB capsule and diclofenac sodium in buffered aqueous solution. The extent of availability of diclofenac from the HGB capsule was only 59 per cent relative to that from the solution (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Nitroglycerin absorption from transdermal systems: formulation effects and metabolite concentrations.

We recently compared plasma concentrations of nitroglycerin and its two dinitrate metabolites in 16 healthy male subjects after application of two controlled-release transdermal formulations of the drug. Analysis of the resulting plasma concentration-time curves indicated that the two formulations did not produce equivalent concentrations of parent drug or either of the dinitrate metabolites during the initial period of dosing. In addition, both formulations produced concentrations of the two dinitrate metabolites that exceeded the concentration of the parent drug by severalfold. Even if the pharmacologic effect of the dinitrate metabolites is low compared to that of nitroglycerin, these higher concentrations may contribute to the effect of nitroglycerin. Scrutiny of the ratio of 1,2-glyceryl dinitrate to 1,3-glyceryl dinitrate in the 16 subjects confirmed previous observations that preferential formation of the 1,2-glycerol dinitrate metabolite may occur depending on the route of administration. This ratio may thus be indicative of the bioavailability of nitroglycerin following transdermal application. Additional data suggesting racial differences in nitroglycerin absorption after transdermal application are presented.

Dosage form and formulation effects on the bioavailability of vitamin E, riboflavin, and vitamin B-6 from multivitamin preparations.

The effects of formulation factors and pharmaceutical dosage form on the bioavailability of RRR-alpha-tocopherol (d-alpha-tocopherol), riboflavin, and pyridoxine hydrochloride were studied after administration of two capsule formulations and a tablet to 12 normal humans. Absorption of RRR-alpha-tocopherol was increased from the Aquabiosorb soft elastic gelatin (SEG) capsule formulation compared with the modified standard-SEG capsule and the commercial tablet. There were no significant differences in bioavailability of riboflavin and pyridoxine hydrochloride between the SEG formulation and the tablet albeit a trend toward consistent absorption was seen from the SEG formulation. The modified-SEG formulation exhibited significantly lower bioavailability for these water-soluble vitamins. The enhanced bioavailability of vitamin E and the trend towards faster and more consistent absorption of riboflavin and vitamin B-6 from the SEG formulation may be related to the surfactant vehicle employed and the attendant wetting properties. The results also suggest ethnic differences in vitamin bioavailability.

Cost containment using cysteine HCl acidification to increase calcium/phosphate solubility in hyperalimentation solutions.

The purpose of this study was to determine if (1) the calcium/phosphate insoluble product was inversely related to pH [when cysteine HC1 (CH) was added as neonatal supplementation at 0.5 mM/kg/day to hyperalimentation (HAL) solutions] and (2) the potential cost savings to the hospital. The pH of the HAL solutions was adjusted by adding various amounts of CH to the HAL solution. HAL solutions containing 27 mEq of calcium/liter and 30 mEq (15 mM) of phosphate/liter were compounded. Ten-milliliter aliquots were analyzed at 0, 12, 24, and 48 hr. All samples (n = 56) were filtered (0.22 mu), viewed with 7-10,000 X magnification scanning electron microscopy, and qualitatively analyzed with a Philips Energy Dispersive X-Ray Analysis System equipped with a SW9100 Microprocessor. Calcium/phosphate insoluble product was present in the 0-, 12-, 24-, and 48-hr samples from the CH-free solutions. The solutions containing 759 mg (4.17 mM)/liter of CH however, remained free of precipitant. This investigation demonstrated that addition of CH to HAL can foster significant cost containment (projected $82,000/yr tangible hospital savings) by the elimination of current calcium/phosphate separation procedures for neonates on parenteral nutrition.

Bacterial endotoxin retention by inline intravenous filters.

Filters used in i.v. administration sets were tested for their ability to retain bacterial endotoxins for up to 96 hours of continuous infusion. Inline filters composed of cellulose ester, polyacrylate, polypropylene, polyethylene, or Posidyne Nylon 66 were used during continuous infusion of 5% dextrose injection at 83 mL/hr. One milliliter of inoculum containing 10(8) Escherichia coli was injected through a port upstream from the filter. A bacterial filter was used to monitor the sterility of effluent from the inline filters. The effluent was tested with limulus amebocyte lysate (LAL) that could detect endotoxin concentrations greater than 50 pg/mL. A control solution was monitored for viability of the bacteria throughout the course of the study, and positive endotoxin controls were used to confirm the sensitivity of the LAL. Samples of effluent were tested at 0, 4, 19, 24, 48, 72, and 96 hours. Effluent from all filters was sterile throughout the study. LAL assay indicated that only the effluent from filters containing Posidyne Nylon 66 was free of endotoxins for 96 hours. Effluent from the other filters contained endotoxins immediately after injection of the E. coli. Of the inline filters tested, only the one composed of Posidyne Nylon 66 was able to retain E. coli endotoxin for 96 hours. Further study is needed with E. coli and other microorganisms that are likely contaminants of i.v. infusions.

Pharmacokinetic-pharmacodynamic modelling and simulation using the electrical circuit simulation program SPICE2.

The use of the electrical circuit simulation program SPICE2 for performing digital computer simulations of linear and non-linear pharmacokinetic-pharmacodynamic models is described. SPICE2 utilizes the principles of network thermodynamics (thermodynamics of electrical circuits). These principles dictate analogy between the conservation laws of chemical reactions and mass transport and Kirchhoff's laws of current and voltage balance, and also prove that Fick's law of diffusion is isomorphous with the conductance form of Ohm's law. Detailed descriptions of program inputs, formats, and options for simulation of linear and non-linear pharmacokinetic-pharmacodynamic systems are provided, with appropriate examples. Single as well as multiple dose simulations (accumulation kinetics and dynamics) are discussed. The advantages of SPICE2 over other available simulation packages, including user-friendliness, ease of operation, versatility, power, and the economy of time and effort afforded, are emphasized. The educational value of SPICE2 as a highly versatile tool for teaching both fundamental and complex pharmacokinetic-pharmacodynamic concepts, as well as its routine usage in elucidating complex research problems, are also discussed.

Dynamic simulation of pharmacokinetic systems using the electrical circuit analysis program SPICE2.

The electrical circuit simulation program SPICE2 is used to perform computer simulations of linear and non-linear pharmacokinetic systems. This is achieved by applying novel network thermodynamic principles which make use of the analogy between the conservation laws of chemical reactions and mass transport and Kirchoff's laws of current and voltage balance for electrical circuits. A simple description of program input for general pharmacokinetic simulation as well as simulation of complex pharmacokinetic and physiologic phenomena such as single and multiple divided daily dosing, Michaelis--Menten kinetics, gastric emptying cycle, drug resorption and linear and non-linear drug protein binding is provided. Drug concentrations or amounts in different compartments are graphically obtained or tabulated as time functions. The economy of time and effort afforded by this program is illustrated by simulating the metabolism and accumulation kinetics of salicylic acid on single and repeated divided dosing. The advantages of SPICE2 over other available simulation packages and its educational value as a teaching and research tool are discussed.

Michaelis-Menten absorption kinetics in drugs: - examples and implications.

It is shown that the absorption of phenylbutazone, naproxen, and chlorthiazide is governed by a dose limiting mechanism. This dose dependency may be explained by a saturation absorption process mathematically obeying Michaelis-Menten type kinetics. Observed dose relationships for tetracycline, fenclozic acid and related compounds, phenytoin, and possibly digoxin and digitoxin may be explained if a saturable process in absorption is postulated. This behavior may be produced by insolubility of the drug compound, a limited "window of absorption" in the gastrointestinal tract, or a capacity limited absorption because of the carrier or the transport mechanism involved. The need for suitably designed dose response studies with new drug compounds is discussed.