Effect of pH changes and ethanol on the binding of tricyclic antidepressants to cholestyramine in simulated gastric fluid.

Tricyclic antidepressants have previously been shown by this laboratory to bind significantly (greater than 80%) to cholestyramine in 1.2 mol/L HCl, used to simulate gastric fluid. This finding has important implications for individuals using tricyclic and cholestyramine concurrently, and it may also have potential therapeutic implications in the treatment of tricyclic overdose. In the present study the effects of pH changes and ethanol on this binding were evaluated. Percent binding of amitriptyline, desipramine, doxepin, imipramine, and nortriptyline decreased from 75-90% (pH 1.0) to 35-50% (pH 4.0). Beyond pH 4.0, however, the binding of each antidepressant increased up to 60-75% at pH 6.5. In contrast, ethanol consistently reduced the percent binding of each antidepressant to cholestyramine in 1.2 mol/L HCl until, in the presence of pure ethanol, the binding ranged from 0% (nortriptyline) to only 32% (doxepin). These findings are important since pH varies widely within the gastrointestinal tract and since ethanol may be co-ingested with cholestyramine and antidepressants.     

Photolysis of cyanocobalamin in aqueous solution.

Cyanocobalamin is photolysed in aqueous solution to produce hydroxocobalamin. The kinetics of photolysis has been studied at pH 1-12 using a newly developed spectrophotometric method for the simultaneous determination of the two compounds at 550 and 525 nm or 361 and 351 nm. Cyanocobalamin follows zero-order kinetics at the pH values studied and the rate is catalysed by both hydrogen and hydroxyl ions. The log k-pH profile indicates that cyanocobalamin has maximum stability near pH 7. The cationic species appears to be more susceptible to photolysis than the neutral form. The rate constant for the reaction at pH 1 is 1.32 x 10(-7) mol l-1 min-1 compared with 0.050 x 10(-7) mol l-1 min-1 at pH 7.     

Binding of bile acids to cholestyramine at gastric pH conditions.

The binding of bile salts to cholestyramine was studied under varying conditions of pH and added electrolyte. The taurine-conjugated bile salts were strongly absorbed by the anion-exchange resin at low pH and in the presence of chloride anions. Glycocholic acid binding was very weak at low pH but increased strongly with increasing pH. The presence of chloride ions strongly decreased the amount of glycocholate bound by the anion-exchange resin.     

Spray-dried powders as nasal absorption enhancers of cyanocobalamin.

The aim of this work is to describe and characterize a new spray-drying procedure for the production of nasal powders as an alternative to the conventional freeze-drying method. Cyanocobalamin was chosen as the active ingredient and loaded into five different nonsoluble vehicles with high water absorption ability. Then these hydrated particles were suspended in methylene chloride and spray-dried. Particle size, morphology, true, bulk and tapped density, percentage of compressibility, moisture content, water intake, and drug diffusion were studied and significant differences were obtained depending on the nature of the vehicle. The drying method, either the new spray- or the conventional freeze-drying, was less important. Interestingly, an inverse correlation was found between water uptake and drug diffusion. Microcrystalline cellulose, dextran microspheres, and crospovidone were chosen for an in vivo bioavailability study in rabbits. Three other nasal reference formulations and an intravenous solution were also administered. The spray-dried powders showed higher bioavailability than the three nasal reference formulations. The highest absorption enhancement was observed with cellulose microcrystalline powders, which provided a 25% mean absolute bioavailability, followed by crospovidone and dextran microspheres formulations with mean bioavailability values of 14% and 7%, respectively. In conclusion, the new spray-drying method is useful for the production of cyanocobalamin nasal powders.     

Antinociceptive properties of thiamine, pyridoxine and cyanocobalamin following repeated oral administration to mice.

Following repeated oral administration for 7 days thiamine (thiamine nitrate, CAS 532-43-4), pyridoxine (pyridoxol hydrochloride, CAS 58-56-0), and cyanocobalamin (CAS 68-19-9) exhibited at high dose levels alone or in combination dose-related antinociceptive properties in the writhing test in the mouse. Cyanocobalamin exerted a potentiating effect in the combination of the 3 vitamins.     

Enhanced elimination of warfarin during treatment with cholestyramine.

1 The elimination and anticoagulant activity of a single intravenous dose of warfarin (1.0-1.2 mg/kg) without and with concomitant cholestyramine treatment (about 4 g three times daily) was studied in five healthy male subjects. 2 Cholestyramine treatment decreased the biological half-life of plasma warfarin (from a mean value of 2 days -1.3 days) and increased the total clearance of this drug (from a mean value of 37 ml kg-1 day-1--53 ml kg--1 day--1). 3 The total anticoagulant effect per dose of warfarin, as measured by the area under the effect v time curve, was also reduced by cholestyramine (average reduction of about 25%). 4 Warfarin possibly undergoes enterohepatic recycling in man which can be interrupted by cholestyramine.     

Interaction of tricyclic antidepressants with cholestyramine in vitro.

The adsorption of amitriptyline, desipramine, doxepin, imipramine, and nortriptyline onto cholestyramine was demonstrated in vitro with use of 1.2 mol/L HCl at 37 degrees C to simulate gastric fluid. Binding to cholestyramine was approximately 80% for each of the tricyclic antidepressants, and this was about the same degree of binding noted with a nonpharmaceutical, non-ionic resin widely used in the diagnostic toxicology laboratory (Amberlite XAD-2). In contrast, five other non-antidepressants (acetaminophen, chlordiazepoxide, procainamide, quinidine, and theophylline) showed only minimal binding to cholestyramine under these conditions. Activated charcoal completely bound all drugs studied. These findings suggest that cholestyramine should be used with caution in patients receiving tricyclic antidepressants. They also suggest that cholestyramine may be a potentially useful adjunctive therapy in treatment of overdose with the tricyclic antidepressants.     

Stability of cyanocobalamin in sugar-coated tablets

The purpose of this study was to clarify the stability of cyanocobalamin (VB(12)-CN) in sugar-coated tablets containing fursultiamine hydrochloride (TTFD-HCl), riboflavin (VB(2)), and pyridoxine hydrochloride (VB(6)), and to identify the factors affecting the stability of VB(12)-CN in these sugar-coated tablets. The stability of VB(12)-CN was investigated using high-performance liquid chromatography while decomposition was evaluated kinetically. The decomposition of VB(12)-CN in sugar-coated tablets with high equilibrium relative humidity (more than 60%) under closed conditions showed complex kinetics and followed an Avrami-Erofe'ev equation, which expresses a random nucleation (two-dimensional growth of nuclei) model. We showed that equilibrium relative humidity, the incorporation of VB(2) and VB(6), and sugar coating, are the main factors influencing decomposition and that these factors cause the complex decomposition kinetics.     

Interaction of naproxen with cholestyramine

‘In vitro’ and ‘in vivo’ studies were used to determine the interaction of naproxen, an anti-inflammatory agent, and cholestyramine, a hypocholesterolemic substance. Cholestyramine shows a marked affinity for naproxen and the intensity of this is governed by the pH values. The maximum amount of naproxen adsorbed by the resin is close to 2·2 mMg^?1. The pharmacokinetics of naproxen was studied in eight healthy volunteers after concurrent oral administration in a single dose of 250 mg of naproxen and 4 g of cholestyramine. The resin causes an important delay in the incorporation of naproxen into the systemic circulation, though no significant modifications are seen to take place in any other pharmacokinetic parameters of the drug.     

In vitro assessment of the mucoadhesion of cholestyramine to porcine and human gastric mucosa.

Previous in vivo studies have suggested that the extended gastric residence and uniform intragastric distribution of cholestyramine may be due to mucoadherent properties. This series of in vitro investigations explored the possibility of the anion exchange resin exhibiting bioadhesive behaviour, and investigated the characteristics, such as particle size and surface charge, that may affect it. Tensile strength measurements were carried out to determine the mucoadhesion of cholestyramine and other test materials (resin particulates, polymers and hydrogels) with varying adhesive properties, to isolated porcine and human gastric mucosa. Optimal instrumental parameters for the system were determined initially and used; all procedures were carried out at room temperature (22 degrees C). The particle size of cholestyramine did not affect mucoadhesion to either porcine or human gastric mucosa (P=0.673, porcine; P=0.969, human), whilst anionic exchangers were found to provide better mucoadhesion than cationic exchangers (P=0.0002, porcine; P=0.0009, human). In some instances, it was found that the detachment forces recorded were lower with human gastric mucosa than with porcine gastric mucosa, although this was not consistently statistically significant. A rank order of mucoadhesion was constructed from a comparison of cholestyramine with eight other test materials. Cholestyramine produced the second highest degree of mucoadhesion, with Carbopol producing the greatest adhesion. Dextran and polyethylene glycol did not display good mucoadhesion under these conditions. From the findings presented here, we have found that cholestyramine demonstrates good mucoadhesion to both porcine and human gastric mucosa when compared to other known bioadhesives. It is suggested that particle size does not contribute to this mucoadherent behaviour but the surface charge of the resin has a significant part to play.     

Metabolic effects of clofibrate and of cholestyramine administration to dogs

Dogs were given clofibrate, 50 mg/kg of body weight/day for 6 days or 50 mg/kg of body weight/day for 2 days, followed by 40 mg/kg of body weight every 30–36 hr over an additional 9-day period. Cholestyramine, 0.7 g/kg of body weight/day, was administered to an additional group of dogs over an 11-day period. Plasma cholesterol concentrations in dogs treated with clofibrate for either 6 or 11 days decreased 24 per cent and decreased 16 per cent in dogs given cholestyramine. ¹⁴C incorporation into bicarbonate from 3-¹⁴C-pyruvate, from [U-¹⁴C]-L-alanine and from [1-¹⁴C]glucose was significantly increased by liver slices from clofibrate-treated dogs when compared with tissue from control animals, but cloflbrate did not result in any changes in [¹⁴C]cholesterol or [¹⁴C]fatty acid formation from either [3-¹⁴C]pyruvate or from [U-¹⁴C]alanine. [¹⁴C]Cholesterol formation from 6-[¹⁴C]glucose was virtually abolished in liver slices taken from dogs treated with clofibrate for 11 days. Liver slices from dogs treated with cholestyramine showed a 3.5- to 4.0-fold increase in ¹⁴C incorporation into cholesterol from both [3-¹⁴C]pyruvate and [6-¹⁴C] glucose, and a significant increase in ¹⁴C incorporation from [1-¹⁴C]glucose into bicarbonate. Clofibrate administration resulted in decreased liver glycogen concentrations and decreased ¹⁴C incorporation into glycogen from [¹⁴C]glucose, but ¹⁴C incorporation into glycogen from [U-¹⁴C]L-alanine was unaffected. If the hypocholesterolemic effect of clofibrate in dogs results from decreased cholesterol synthesis, changes in glucose metabolism may form the metabolic basis rather than alterations in pyruvate (or acetyl CoA) metabolism.     

Enzymatic decyanation of cyanocobalamin in rat tissues

Cyanocobalamin is decyanated in vitro to hydroxocobalamin by rat liver and kidney. This appears to be due to an enzyme system which we have called “cyanocobalamindecyanase”. The enzyme is in the soluble fraction of the cells; it requires reduced cozymases and flavins and has an optimum pH of 7.2 under anaerobic conditions. This is consistent with the fact that conversion of cyanocobalamin to hydroxocobalamin and/or its reduced forms (B₁₂r, B₁₂s) involves a reductive process in the earliest stage of the biosynthesis of coenzyme B₁₂.     

Comparison of the bioavailability of cyanocobalamin from capsule and liquid dosage forms.

Comparative in vivo absorption of cyanocobalamin from two dosage forms, gelatin capsule and liquid, was studied. Forty-two subjects received simultaneous doses of cyanocobalamin in capsule and liquid form, labeled with cobalt-57 and cobalt-60, respectively. Excretion, a measure of absorption, was between 2 percent and 66 percent greater with the liquid form. In vitro dissolution studies showed that the capsules had a tendency to collapse into a stringy mass and to dissolve slowly.