Percutaneous absorption of diclofenac sodium ointment

In order to allow a high concentration of the drug to reach the lesion, preventing disorders in the digestive tract as a result of the oral administration of an anti-inflammatory steroid-type agent and to attain a sufficient plasma concentration to obtain an effective systemic effect, we prepared ointments and studied the percutaneous absorption of the drug in rabbits. Diclofenac sodium was rarely absorbed precutaneously when given as a simple ointment, hydrophilic ointment, absorption ointment, macrogols ointment described in the Japanese Pharmacopoeia, and carboxyvinylpolymer as gel ointment were used as the ointment bases. Therefore, we used a gel ointment made with methylcellulose as the ointment base and added isopropyl myristate to it as a sorbefacient, obtaining a good plasma concentration. Using the values obtained by the intravenous injection of diclofenac sodium, the parmacokinetics of the plasma concentration obtained by the percutaneous absorption was studied by two-compartment models containing two first-order rate constants. In addition, the retention of this drug in skin and the test for the loss of water and ethanol from the ointment were studied.     

A quantitative approach to the determination of drug release from reverse-phase evaporation lipid vesicles. The influence of sodium ion-pair formation on warfarin partitioning and permeability

The influence of sodium ion-pair formation on warfarin partitioning and permeability has been investigated using reverse-phase evaporation lipid vesicles. An experimental method for the isolation of the vesicles having known amounts of encapsulated drug has been described. The partitioning of warfarin between phospholipid membrane and aqueous phase at different Na⁺ concentrations was determined in separate experiments. Thus, using a two-compartment cylinder assembly the influence of Na⁺ concentration on the release rate of the encapsulated warfarin from the vesicles could be measured quantitatively. It appears that under the present experimental conditions warfarin partitioning does depend on Na⁺ concentration whereas vesicle permeability towards warfarin does not seem to be affected.     

Population pharmacokinetics/pharmacodynamics of linezolid in sepsis patients with and without continuous renal replacement therapy

Purpose

The purpose of this study was to identify the optimum dosing regimen of linezolid in sepsis patients with and without renal dysfunction and sepsis patients on low-dose continuous renal replacement therapy (CRRT) using a pharmacokinetics/pharmacokinetics (PK/PD) approach.

Absorption and dissolution of nitrofurantoin from different experimental formulations

The general applicability of the polyvinylpyrrolidone, polyethylene glycol, mannitol and sorbitol solid dispersion and co-precipitation technique as a method for enhancing the gastrointestinal absorption of orally administered hydrophobic drugs was explored with the urinary antiseptic nitrofurantoin. The in vivo absorption patterns of pure nitrofurantoin and the test preparations were compared by following the cumulative amount of nitrofurantoin excreted in the urine as a function of time. The results of these urinary excretion studies demonstrated that the absorption of nitrofurantoin in man from the test systems was significantly enhanced and was present in the body at much higher levels than when equivalent doses of either the drug alone or as physical mixture were orally administered. A correlation was found between the in vitro dissolution rates of these test systems at 37°C and their in vivo absorption data.     

Simultaneous determination of piroxicam and its main metabolite in plasma and urine by high-performance liquid chromatography

A rapid and sensitive high-performance liquid Chromatographic procedure is described for the simultaneous determination of piroxicam and its main metabolite, such as 5′-hydroxypiroxicam, in plasma and urine. Acidified plasma (pH 3.0) was extracted with ethyl ether and indomethacin was used as an internal standard. The organic extract was reduced to dryness, the resultant residue redissolved in the mobile phase, and aliquots of this solution chromatographed on a Lichrosorb RP-18 (7 μm) column using a mobile phase consisting of an acetonitrile-water-acetic acid (58:38:4) mixture. The flow rate was 1.2 ml/min and the effluent was monitored at 365 nm with 0.02 aufs. The sensitivities of this method were 0.05 μg/ml levels of piroxicam and 5′-hydroxypiroxicam in the plasma and urine samples.     

Percutaneous absorption of phenylbutazone from ointment bases in rabbits

A rapid, sensitive, accurate and reproducible assay procedure for the simultaneous separation and determination of phenylbutazone and oxyphenbutazone is proposed using reversed-phase, high-pressure liquid chromatography and UV detection. Acidified plasma (pH = 5) was extracted with cyclohexane-ether (1:1) and indomethacin was used as an internal standard. Plasma phenylbutazone levels after oral and intravenous drug administration were described by the two-compartment model. A pharmacokinetic model, similar to the percutaneous absorption of indomethacin, was developed to test concepts regarding the percutaneous absorption of phenylbutazone from topical ointment bases. A reasonably good agreement between experimental and calculated values was obtained by taking into account such factors as the absorption rate constant (k_a), the drug release rate constant (k_r) and the fraction of drug absorbed (F). The ointment bases selected for study were solution-type and suspension-type ointment bases. The good percutaneous absorption of phenylbutazone after the topical administration was obtained by using the absorption base.The optimal effect with additives in the absorption ointment base was finally attained with the addition of 1 % urea. The changes in site and size of application of the phenylbutazone ointment was also investigated and the following was found: dorsal site > abdominal site > thigh site. Increasing the size of the application area increased the percutaneous absorption of phenylbutazone.     

Variations in dissolution rates of sugar-coated chlorpromazine tablets

The dissolution rates of 14 batches of sugar-coated chlorpromazine tablets (10, 25 and 100 mg) were examined by the U.S.P. method. Although all the batches passed the U.S.P. disintegration test in 0.1 N HCl, none passed the U.S.P. dissolution limit (not less than 80% dissolution after 30 min). Poor dissolution rates were ascribed to delayed break-up of the sugar-coat. The dissolution and dialysis rates of tablets of one batch were dependent on the medium composition suggesting possible drug- excipient interaction.     

Gastric emptying and intestinal transit of non-disintegrating capsules—the influence of metoclopramide

Differential Scanning Calorimetry (DSC) was employed to identify and define the interaction between ibuprofen and stearic acid, stearyl alcohol, calcium stearate and magnesium stearate. All stearates were found to form simple eutectics with ibuprofen, and phase diagrams for each system were constructed.     

Improvement of dissolution and absorption characteristics of phenytoin by a water-soluble β-cyclodextrin-epichlorohydrin polymer

Complexes of phenytoin with 3 water-soluble cyclodextrin-epichlorohydrin polymers (α-CyD · EP β-CyD · EP and γ-CyD · EP) in aqueous solution and in the solid phase were studied by a solubility method spectroscopic analyses and X-ray diffractometry. Binding to CyD polymers increased the solubility and dissolution rate of phenytoin in the order of $\text{β-}\text{CyD}\text{·}\text{EP}\text{> α-}\text{CyD}\text{·}\text{EP}\text{≧ γ-}\text{CyD}\text{·}\text{EP}$. The rapidly dissolving form of phenytoin-β-CyD · EP complex was found to significantly increase the plasma levels of the drug after oral administration to dogs. Data are presented suggesting that β-CyD · EP is particularly useful for improving the oral bioavailability of phenytoin.     

Protective action of diethyldithiocarbamate and carbon disulfide against renal injury induced by chloroform in mice

Oral administration of diethyldithiocarbamate (DTC) and carbon disulfide (CS2) protected mice against CHCl3-induced kidney injury, as evidenced by normalization of delayed plasma phenolsulfonphthalein clearance, suppression of increased kidney calcium content and prevention of renal tubular necrosis. In CCl4-treated mice, in which liver microsomal monooxygenase activities were decreased markedly, and kidney microsomal aniline hydroxylase and p-nitroanisole demethylase activities were increased to about twice those of the untreated mice, renal toxicity of CHCl3 was greatly potentiated, and the latter effect was also blocked by both agents. DTC and CS2 per se markedly decreased kidney microsomal aniline hydroxylase and p-nitroanisole demethylase activities at 1 hr after oral administration, accompanying a moderate loss of cytochrome P-450 content, in both normal and CCl4-treated mice. The protection was not due to hypothermia, because pretreatment with DTC or CS2 (p.o.) also prevented the hypothermia induced by CHCl3. The mechanism of the protection may have involved inhibition of metabolic activation of CHCl3 in the kidney rather than in the liver.     

Formation,bioavailability and organoleptic properties of an inclusion complex of femoxetine with β-cyclodextrin

Femoxetine, a new selective serotonin uptake inhibitor with antidepressant properties, possesses a very bitter taste which hinders the development of oral liquid formulations. The present study has shown that it is possible to improve the organoleptic properties by inclusion complexation of the drug with β-cyclodextrin. Phase solubility diagrams and UV-spectroscopic studies revealed the formation of 1 :1 and 1: 2 inclusion complexes, the strongest complex being obtained for femoxetine in free-base form. A microcrystalline inclusion complex was isolated and shown to have the stoichiometric composition of 1: 2 (femoxetine: β-cyclodextrin). In a single dose cross-over study in 5 volunteers, the bioavailability of the solid complex formulated as an aqueous suspension was found to be similar to that observed for a sugar-coated tablet of femoxetine hydrochloride.     

Thermodynamics of distribution of para-substituted phenols between organic solvents and sodium chloride solution

The distribution of para-substituted phenols between 8 organic solvents and 0.15 mol · dm⁻³ NaCl solution has been determined at five different temperatures using the shake-flask technique and the thermodynamic parameters for the process (ΔH and ΔS) evaluated from the van't Hoff isochore. The free energy change for the transfer of the methylene group from water to organic solvent was entropically controlled. Logarithms of distribution constants of phenols for a given organic solvent—water system were linearly related to those for other solvent systems and also to the substituent constant of Hansch. The influence of the nature of the organic solvent upon the distribution constants of phenols and the incremental distribution constants per methene group could be evaluated by the Regular Solution theory.     

Studies on the biliary excretion mechanisms of drugs. II. Biliary excretion of thiamphenicol, chloramphenicol and their glucuronides in the rat

Thiamphenicol (TP) or chloramphenicol (CP) administered intravenously (14 μmoles) to rats with ligated renal pedicles is rapidly excreted in bile mostly as the glucuronide (about 23 and 75 per cent in 7 hr respectively). Increasing the dose of either drug does not result in an increased excretion of glucuronide, indicating that the excretion process is saturable. TP glucuronide (TPG) or CP glucuronide (CPG) administered intravenously to rats with ligated renal pedicles is rapidly excreted into bile in high concentration as unchanged glucuronide. The maximal excretion rate of TPG or CPG (about 14.0 and 18.0 gmmoles/10 min respectively) when each glucuronide (100 μmoles) was administered is much higher than that (about 5.1 and 8.5 gmmoles/10 min respectively) when each aglycone (200 μmoles) was administered. The results suggest that the transport maxima (Tms) for the biliary excretion of TP and CP are due to a saturation of the conjugating process. CPG used in this study is isolated by a new method.     

Effects of ethanol and lead ingestion on urinary sodium excretion and related enzyme activity in rat kidney

The present study was undertaken to examine lead-ethanol interaction with respect to previously reported lead enhancement of urinary Na⁺ excretion [Y. Suketa, S. Hasegawa and T. Yamamoto, Toxic. appl. Pharmac.47, 203 (1980)]. Simultaneous administration of ethanol reduced the enhancement due to lead alone. A decrease in serum Na⁺ concentration followed lead administration and the decrease appears to be less when ethanol was administered simultaneously. Renal (Na⁺ + K⁺ATPase activity was suppressed after lead administration, but it was stimulated after ethanol administration. the suppression of renal (Na⁺ + K⁺ATPase activity after lead administration was diminished after simultaneous administration of ethanol and lead. the diminution of the suppression appeared to be associated with a corresponding reduction in urinary Na⁺ excretion.     

Calcium and 1-hydroxyethylidene-1,1-bisphosphonic acid: polynuclear complex formation in the physiological range of pH

1-Hydroxyethylidene-1,1-bisphosphonic acid (HEDP) is used in a variety of diagnostic, research and therapeutic applications at in vivo concentrations of from < 1 μ M to > 1 mM. Previous studies have shown that calcium and HEDP form polynuclear aggregate complexes at high pH. Calcium ion titrations at constant pH 8.0, and pH titrations at 1:1 and 2:1 ratios of total calcium to total diphosphonate, provide evidence for the occurrence of aggregation of calcium and HEDP under physiological conditions. A robust feature of several polynuclear models examined is a dramatic pH dependence of polynuclear species concentrations between pH 5.5 and 7.0.     

Protective effect of diethyldithiocarbamate and carbon disulfide against liver injury induced by various hepatotoxic agents

Diethyldithiocarbamate (DTC) and carbon disulfide (CS2), at nearly equimolar oral dose levels, protected mice against liver damage induced by carbon tetrachloride, chloroform, bromotrichloromethane, thioacetamide, bromobenzene, furosemide, acetaminophen, dimethylnitrosamine and trichloroethylene, as evidenced by the suppression of elevations in plasma GPT activity and liver calcium content, and of histopathological alterations. Both agents also prolonged hexobarbital sleeping time and zoxazolamine paralysis time in mice. DTC and SC, alone, given orally, decreased microsomal metabolism of several substrates (aniline, p-nitroanisole, hexobarbital, zoxazolamine, aminopyrine and 3,4-benzopyrene), CC14-induced lipid peroxidation, and cytochrome P-450 content. The loss of microsomal drug-metabolizing enzyme activity was also observed in the experiments in vitro using liver slices and isolated microsomes. Since a characteristic common to such diverse hepatotoxins is that they require metabolic activation before exhibiting hepatotoxicity, the protective mechanisms of DTC and CS2 may involve their interference with the process of metabolic activation of these hepatotoxins. The protective action of DTC may be mediated almost entirely through CS2 when administered orally and at least partly with parenteral administration, since, in CCl4-induced liver injury, DTC was most effective when given orally, while the action of CS2 was less dependent on the route of administration. Thus CS2 and CS2-producing agents in vivo such as dithiocarbamate derivatives and disulfiram may modify toxicological and pharmacological effects of foreign compounds by inhibiting microsomal drug-metabolizing enzyme activity in the liver.     

Application of automated flow injection analysis (FIA) to dissolution studies

The application of FIA to dissolution studies is described. Propantheline bromide, salicylamide and sulfamethizole were chosen as model drugs to investigate the utility of FIA method for dissolution studies. In each case the FIA system with the appropriate chemistry manifold was coupled with the rotating basket apparatus, A fully automated monitoring of dissolution rates was achieved. A complete dissolution profile in tabulated form is provided by the computer of the system at the end of the experiment.

Automation of any type of solid dosage forms agitation technique can be easily acquired by adapting a FIA system.     

Hepatic transport of indocyanine green in rats chronically intoxicated with carbon tetrachloride

Hepatic transport of indocyanine green (ICG) and probable factors altering the disposition of ICG were examined in rats chronically intoxicated with carbon tetrachloride. Delays were shown in both plasma disappearance and biliary excretion of ICG in intoxicated rats. No significant difference was shown in the total amount of ICG bound to the plasma proteins. In the intoxicated rats, significant decreases were observed in the pharmacokinetic parameters, k₁₂, k₃₄ and V₂, calculated by a three-compartment model, while a significant increase was observed in k₂₁; V₁ was not altered. In both the control and intoxicated rats, the values of k₁₂·V₁ were significantly smaller than the hepatic plasma flow, and it was suggested that the plasma flow does not play a primary role in the hepatic uptake of ICG. No significant difference was observed in the elution profiles of the 100,000 g supernatant fraction on a Sephadex G-75 column, and ICG bound mainly to the X-fraction in both the control and intoxicated rats. About 90 per cent of the ICG administered intravenously was distributed to the 9000g precipitate fraction by 5 min in both groups of rats. It was concluded that a decrease in the permeability of the sinusoidal plasma membrane of the hepatocyte may explain the decrease of ICG uptake rate by the livers of the intoxicated rats.