Ditheophylline succinate: transfer of theophylline across everted rat intestinal sacs.

The cumulative theophylline transfer rate across 10-cm everted rat intestinal sacs incubated at 37 degrees in pH 7.4 Krebs phosphate buffer was determined. A suspension of ditheophylline succinate ( a potential prodrug of theophylline) and a solution of theophylline at equimolar concentration were evaluated to determine the magnitude of the difference between the cumulative theophylline transfer rates from the two preparations. A linear concentration dependency for the rate across the intestinal wall was evidenced. The theophylline formation rate from ditheophylline succinate suspended in pH 7.4 Krebs buffer at 37 degrees followed apparent zero-order kinetics. The observed difference (fourfold) between the cumulative transfer rates estimated for the theophylline solution and the ditheophylline succinate suspention was attributed to the prevailing theophylline concentration in the mucosal solutions. The biopharmaceutical implication of these observations are discussed.

Vehicle effects on activity of an anticonvulsant compound.

The effect of several lipid and nonlipid pharmaceutical solvents on the in vivo activity of 1-diphenylmethyl-4- [(6 methyl-2-pyridyl) methyleneamino] piperazine (I) was evaluated in the mouse. The intensity of onset and the duration of anticonvulsant activity of the compound were affected depending on th type and form of liquid dosage preparation used. The rate of decline in anticonvulsant activity in the 80-20% response range followed apparent zero-order kinetics. A linear relationship between the observed ED50 and the concentration of sorbitol in the dosage form of I was observed. A reduction in the sorbitol content of the dosage form resulted in a proportional increase in the rapidity of onset and the duration of anticonvulsant activity of I. Emulsification restored both the onset and duration of pharmacological activity, which was virtually arrested when the compound was given orally as a solution in oil.

In vitro and in vivo availability of spironolactone from oral dosage forms.

Tablet formulations of spironolactone with hydrochlorothiazide were studied in vitro and in vivo to evaluate the effect of formulation parameters on the bioavailability of spironolactone. The time required for 50% tablet dissolution (T50) in simulated gastric fluid was linearly correlated with the disintegration times of four experimental formulations and one commercial tablet of spironolactone and hydrochlorothiazide. Bioavailability studies were conducted in four healthy, female beagle dogs. The mean time to peak concentration of canrenone,f cancrenone, the major metabolite of spironolactone, was proportional to the T50 dissolution parameter. A study of spironolactone administered orally with and without hydrochlorothiazide showed that the bioavailability of spironolactone is not affected by hydrochlorothiazide. No significant difference in the bioavailability of spironolactone from one 100-mg and four 25-mg tablets were observed. Estimates of some pharmacokinetic parameters for canrenone closely agreed with those previously reported.

Photochromism of an anticonvulsant, 1-diphenylmethyl-4-(6-methyl-2-pyridylmethylene-amino) piperazine, in the solid state.

The light-induced color change of 1-diphenylmethyl-4-(6-methyl-2-pyridylmethyleneamino) piperazine in the solid state was investigated. Light in the 420-700-nm visible region had no effect. Elevated temperature, dissolution, or prolonged storage in the dark at room temperatures restored the intrinsic color of the compound. IR, UV (solution), NMR, differential scanning calorimetry, and GC methods showed no detectable difference between the long wave-length UV light-exposed (yellow) and unexposed (colorless) samples of the pure compound. Long wavelength UV light exposure studies with several substituted piperazine analogs revealed a structure-activity requirement for the color conversion process. The data indicated that the transformation process from colorless (or faint yellow) to bright yellow is photochromism (phototropy) and is dependent on the intensity of the "action spectrum" in the 300-400-nm region. Studies in the solid state showed that heat-induced fading of the color followed apparent zero-order kinetics. The energy of activation, Eb, for the photochromic conversion process from the metastable (yellow) to the stable (colorless) state was estimated to be about 19 kcal/mole.

In vitro adsorption of diphenoxylate hydrochloride on activated charcoal and its relationship to pharmacological effects of drug in vivo. I.

The adsorption of diphenoxylate hydrochloride, a potent antidiarrheal agent, on activated charcoal powder was studied in vitro. Langmuir adsorption isotherms were established at pH 4 and 7, and the maximum adsorption capacity of charcoal for this drug was estimated using these values. Activated charcoal modified the bioavailability of diphenoxylate hydrochloride in vivo. The antipropulsive action of diphenoxylate in the mouse was strongly inhibited in the presence of activated charcoal. A comparative evaluation of charcoal and chromium oxide used as inert, nonabsorbable markers revealed that chromium oxide may be the marker of choic in GI transit studies in laboratory animals since it does not influence the bioavailability of diphenoxylate hydrochloride.

Binding of metronidazole and its derivatives to plasma proteins: an assessment of drug binding phenomenon.

Metronidazole and four derivatives were studied in vitro to investigate the differences in the extent of their binding to plasma proteins. Modification at the terminal portion of the alkyl side chain resulted in wide differences in the extent of binding. Molecular orbital calculations were performed by the CNDO and MINDO/2 methods to estimate the frontier electron density on the hetero atom at the 3'-position of the alkyl side chain. A linear correlation between the protein binding parameter (loge P) and the frontier electron density (qr) was observed for the binding of this group of trichomonicidal drugs. NMR spectroscopy was used to demonstrate that the alkyl side chain participated in the binding of these compounds to plasma proteins.

Interaction of metronidazole with metallic ions of biological importance.

The possibility tht metronidazole exerts several of its biological actions via interaction with important metal ions was investigated. NMR spectroscopy and polarography (ac) were used to test for any interaction, to locate the probable sites for complexation, and to determine the molecular stoichiometry of any complexes formed. Of the series of divalent metal ions tests, only cupric ion showed detectable interaction with metronidazole. The predominant site of interaction of cupric ion was the unsubstituted nitrogen atom (N-3) on the metronidazole molecule. The stoichiometry of the complex was (Cu-(metronidazole)4)+2. A likely structure for the complex is presented.