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Biomedical subjects

A Yacobi

Publications and source records attributed to A Yacobi.

At least 73 records · Page 4Linked to original sources
PubMed1981

The assessment of the intrasubject variability in digoxin absorption in man from two oral dosage forms.

The reproducibility of drug absorption within a given subject as well as the evaluation of bioavailability of two digoxin dosage forms were studied. The data showed (a) a higher initial plasma digoxin concentration after the soft elastic gelatin (SEG) capsule; (b) a more irregular absorption after the tablet; (c) on the average, the coefficients of variation of individual plasma concentrations were lower after the capsule; and (d) for the capsule, the intrasubject variations of the peak plasma concentrations, time of peak, area under plasma concentrations-versus-time curve (AUC), and amount digoxin excreted in urine (Ae) were on the average 60 per cent of the variations in the tablet parameters. The ratios of AUC and Ae for capsule/tablet were essentially unity, indicating that the amount digoxin absorbed from the 0.4-mg digoxin SEG capsule is identical to that from a 0.5-mg standard reference tablet.

Absorption↗
PubMed1981

Pharmacokinetics of procainamide and N-acetylprocainamide in rats.

The pharmacokinetics of distribution and elimination of procainamide and its major metabolite, N-actylprocainamide, were studied in rats. Eight rats were selected randomly, and each received intravenously 14C-labeled procainamide hydrochloride (75 mg/kg) or 14C-labeled N-acetylprocainamide hydrochloride (86 mg/kg) according to a two-way crossover design. Serial blood samples were withdrawn for 8 hr, and cumulative urine and feces were collected for 48 hr. The plasma concentration-time relationships of procainamide and N-acetylprocainamide were characterized by one- and two-compartment open models, respectively. A pseudo-three-compartment model was necessary to characterize the time course of N-acetylprocainamide in plasma formed after administration of procainamide. The biological half-lives of procainamide and N-acetylprocainamide averaged 0.66 and 2.1 hr, respectively. The urinary excretion profiles of these drugs and the ratio of their biological half-lives in rats were similar to those in humans.

Acecainide↗
PubMed1981

Pharmacokinetics of [14C]bretylium tosylate in rats.

The pharmacokinetics of bretylium tosylate were investigated in eight male Charles River rats. Each animal received an intravenous dose (10 mg/kg) of [14C)bretylium tosylate. Serial blood samples, urine, and feces were collected for up to 72 hr. Bretylium concentrations in plasma and amounts excreted in urine and feces were determined by scintillation counting. On the average, 88 and 95% of the dose were recovered in urine and feces in 24 and 72 hr, respectively. Urinary recovery accounted for 65.6 of the dose while 29.7% was excreted in the feces. Bretylium concentrations in plasma declined triexponentially and were fitted to a three-compartment open model. Bretylium has a very high apparent volume of distribution (15 liters/kg), and its beta half-life averaged 5.5 hr. Mean values of the apparent volume of the central compartment, plasma clearance, renal clearance, and excretion rate constants of bretylium in rats were 1 liter/kg, 1.93 liters/hr/kg, 1.27 liters/hr/kg, and 1.24 hr-1, respectively. The results indicate that: (a) bretylium is strongly bound to the tissues and is eliminated by active urinary secretion and by biliary excretion in rats, and (b) there are strong similarities between the pharmacokinetics of bretylium in humans and rats and that this animal model might be suitable for interaction studies with other drugs.

Animals↗
PubMed1981

Nitroglycerin pharmacokinetics after intravenous infusion in normal subjects.

The purpose of this investigation was to examine the pharmacokinetics of nitroglycerin in normal volunteers after intravenous drug administration. Eight subjects (including one subject on two occasions) received a dose of approximately 0.6 mg iv of nitroglycerin at a rate of 18 micrograms/min. Plasma concentrations of intact drug during and after the infusion were determined using a GLC method. Intra- and intersubject variability in nitroglycerin plasma kinetics was substantial. Generally, however, plasma nitroglycerin disposition was characterized by: (a) a large apparent plasma clearance (0.3-1 liter/min/kg), (b) a large volume of distribution (approximately 3 liters/kg), and (c) a rapid plasma half-life (approximately 3 min). From the apparent volume of distribution obtained, plasma drug can be estimated to account for only approximately 1.3% of total drug in the body. Minor fluctuations in tissue distribution, which can be produced by a myriad of external and internal stimuli, could cause dramatic fluctuation in plasma nitroglycerin concentrations and, hence, in the calculated pharmacokinetic parameters. For example, in two subjects studied, plasma nitroglycerin concentrations oscillated to such an extent that pharmacokinetic analysis could not be performed. In some subjects, steady-state concentrations were not observed in spite of the apparent short plasma half-life, and rebound in plasma concentrations during the postinfusion phase were evident. These phenomena were also observed in other kinetic studies involving organic nitrates.

Administration, Sublingual↗
PubMed1981

Bioavailability of N-acetylprocainamide from mixed diet in rats.

The purpose of this study was to determine the bioavailability of N-Acetylprocainamide (NAPA) from mixed diet in rats. Six groups of 8 male Charles River CD rats received NAPA-HCl as follows: Group I, an intravenous dose (mean 21 mg) of 14C-labelled drug. Group II, in a solution given by oral gavage with and without feed (50 mg) in a two-way crossover fashion. Groups III-VI, incorporated in diet (42-68 mg). Urine and feces were collected for 48 hours and assayed for NAPA and procainamide by a specific HPLC method. On the average, 73% of the drug was eliminated unchanged in urine. Only a small percentage (3-4%) of the intact drug was recovered in feces after intravenous or oral administration. There were no detectable levels of procainamide in urine and feces. The absolute bioavailability of NAPA from oral solution with and without feed was 87 and 90%, respectively, and from the mixed diet was 84-92%. There was no statistically significant difference between the bioavailability of NAPA from solution in fasted and fed rats or from NAPA-mixed diet, indicating that the absorption of the drug in rats was not affected by food. The relative bioavailability of the drug from mixed diet ranged from 94-103%.

Acecainide↗
PubMed1980

Comparative pharmacokinetics of coumarin anticoagulants. XLVI: Effect of treatment of phenobarbital on pharmacokinetics of (S)-(-)-warfarin in rats.

This investigation was carried out (a) to determine if the enzyme inductive effect produced by phenobarbital reduces the interindividual variability in the biotransformation of a drug, as suggested in the literature; (b) to test whether the intrinsic clearance of free drug, for drugs exhibiting restrictive clearance, reflects the activity of drug-metabolizing enzyme systems; and (c) to determine if enzyme induction affects the apparent volume of distribution of a drug that tends to concentrate in the liver. Twelve pairs of adult male rats, matched with respect to their serum warfarin free fraction, received an intravenous injection of (S)-(-)-warfarin, 0.6 mg/kg, after four daily injections of either saline solution or phenobarbital (75 mg/kg). Phenobarbital treatment increased both the total and intrinsic clearance of (S)-(-)-warfarin almost threefold but did not reduce the coefficient of variation of the intrinsic clearance. Serum protein binding of (S)-(-)-warfarin was not affected by phenobarbital treatment. The biological half-life of warfarin and the duration of its anticoagulant effect were reduced substantially by treatment with phenobarbital. Consistent with pharmacokinetic theory, the relationship between total clearance and the free fraction of warfarin in serum remained approximately linear, but the slope of the regression line was increased for the animals treated with phenobarbital.

Animals↗
PubMed1980

GLC determination of bretylium in biological fluids.

Bretylium [(o-bromobenzyl)ethyldimethylamine] is a quaternary ammonium compound used as the tosylate salt for treatment of ventricular fibrillation in humans. A sensitive assay was developed for the determination of low bretylium concentrations in plasma and urine. The internal standards were (p-bromobenzyl)ethyldimethylammonium p-toluenesulfonate and (o-methoxybenzyl)ethyldimethylammonium p-toluenesulfonate. Samples were deproteinized with acetonitrile and extracted with methylene chloride. After the evaporation of the organic phase, the residue was reacted with sodium 2,4,5-trichlorothiophenolate in methanol. This procedure yielded volatile compounds with excellent electron-capture capabilities for the GLC analysis. The assay sensitivity is 5 ng/ml. The extraction recovery of bretylium as determined by a direct radioactivity measurement was 90 and 97% for plasma and urine, respectively. The method is highly reproducible with no significant day-to-day variations. Comparisons of 60 standard plasma samples, 25 standard urine samples, and plasma samples from a dog that received [14C]bretylium showed excellent agreement between the GLC method and direct radioactivity measurement of bretylium.

Animals↗
PubMed1980

Determination of procainamide and N-acetylprocainamide in biological fluids by high-pressure liquid chromatography.

A modification of a high-pressure liquid chromatographic method for the simultaneous determination of procainamide and N-acetylprocainamide in plasma is described. The deficieicies in the specificity of the existing method were overcome by replacing the cation-exchange column and the mobile phase. The recovery and reproducibility of both procainamide and N-acetylprocainamide from human, dog, and rat plasma and urine spiked with either compound were excellent in the concentration range of 0.05--10 microgram/ml for plasma and 0.5--20 microgram/ml for urine. The comparison of this method with a specific extraction method for sets of plasma samples from human subjects and rats receiving N-acetylprocainamide and procainamide, respectively, showed no statistically significant difference.

Acecainide↗
PubMed1980

Evaluation of sustained-action chlorpheniramine-pseudoephedrine dosage form in humans.

This investigation compared the bioavailability of chlorpheniramine and pseudoephedrine from a sustained-action capsule and a combination of two reference standard tablets in 24 normal human subjects. The capsule contained 8 mg of chlorpheniramine maleate and 120 mg of pseudoephedrine hydrochloride, and the tablets each contained half of the amount of the chlorpheniramine or pseudoephedrine in the capsule. Because the capsule was a combination product, a new study design had to be developed to accommodate steady-state conditions for both drugs. Each subject received the capsule (every 12 hr) and the combination of the reference tablets (every 6 hr) for 8 days according to a two-way crossover design. Serial blood and urine samples were taken during the entire study. Plasma and urine samples were assayed for chlorpheniramine and pseudoephedrine by sensitive and specific high-pressure liquid chromatographic or GLC methods. There were no significant differences in the plasma concentration profiles of chlorpheniramine and pseudoephedrine at all times, except when the capsule developed peaks or the tablets developed nadirs. The highest mean peak plasma concentrations for the capsule and the tablets were 38.7 and 32.9 ng of chlorpheniramine/,ml and 525 and 515 ng of pseudoephedrine/ml, respectively. The mean biological half-lives of chlorpheniramine and pseudoephedrine were 21.6 and 8.0 hr, respectively. The AUC and unchanged drug excreted in urine, after a single dose and at steady state, showed that the sustained-action capsule (given every 12 hr) and the reference standard tablets (given every 6 hr) were bioequivalent.

Adult↗
PubMed1980

Pharmacokinetics of bretylium in man after intravenous administration.

The pharmacokinetic profile of bretylium was studied in four normal male volunteers using a new sensitive EC-GC procedure for its quantitative in biological fluids. The plasma concentrations and urinary excretion rates following the constant i.v. infusion of a single 4 mg/kg dose of bretylium tosylate declined biexponentially and the data were fitted to a two-compartment model with a renal and a nonrenal route of elimination. The drug had a mean half-life (t1/2 beta) of 7.8 hr and apparent volume of distribution (Vd, beta) of 8.18 liters/kg. The renal clearance, which was 6 times that of the glomerular filtration rate, accounted for almost 84% of the total body clearance and correlated linearly with the subjects' creatinine clearance. The observed side effects of bretylium were mild and similar to those of other adrenergic blocking agents.

Adult↗
PubMed1980

Effect of coronary artery ligation on the pharmacokinetics of N-acetylprocainamide in dogs.

The effect of ligation of the left anterior descending and septal coronary arteries on the distribution of N-acetylprocainamide (NAPA) was studied in 13 mongrel dogs. The animals received a rapid i.v. infusion of 20 mg/kg NAPA.HCl. In 6 dogs the arteries were ligated simultaneously 10 min after administration of the drug. The other dogs received the same dose without anesthesia or surgery and served as control. Coronary ligation procedure resulted in a significantly higher initial plasma concentration of NAPA, presumably because of a significant decrease in the apparent volume of central compartment. The biologic half-life, the apparent volume of distribution and the total clearance of the drug remained unchanged in both groups of animals. The results of this study suggest that while the pharmacokinetics of elimination of NAPA remain unchanged, the distribution and the effective plasma concentration might be altered by the coronary ligation procedure under anesthesia.

Acecainide↗
PubMed1979

Effect of serum protein binding on sulfisoxazole distribution, metabolism, and excretion in rats.

This investigation determined the effect of serum protein binding on the kinetics of sulfisoxazole distribution, metabolism, and excretion. Adult rats, whose serum free fraction of sulfisoxazole (at a total concentration of 81 +/- 6 micrograms/ml) was 0.05-0.24, received a rapid intravenous injection of 20 mg/kg. Sulfisoxazole concentrations in plasma declined biexponentially with time. There were pronounced and reproducible interindividual differences in the total, metabolic, and renal sulfisoxazole clearances, each positively correlated with the serum free fraction of sulfisoxazole. The renal sulfisoxazole clearance had a component unaffected by serum protein binding. The apparent central compartment volume increased with an increasing serum free sulfisoxazole fraction, but the latter had not apparent effect on the first exponential term of the biexponential equation describing sulfisoxazole elimination kinetics in rats. Serum protein binding was a major determinant of intersubject differences in sulfisoxazole excretion and biotransformation kinetics.

Animals↗
PubMed1979

Urinary excretion of chlorpheniramine and pseudoephedrine in humans.

A specific high-pressure liquid chromatographic method for the determination of chlorpheniramine and pseudoephedrine in urine was developed and applied in a urinary excretion study of normal healthy subjects who received a sustained-release dosage form contianing 8 mgof chlorpheniramine maleate and 120 mg of pseudoephedrine hydrochloride. Five subjects received one dose on Day 1, followed by multiple dosing every 12 hr for 7 days without ammonium chloride administration. Four subjects received one dose of the sustained-release dosage form together with ammonium chloride. Urine samples were collected during the 1st day and at steady state. The method is specific and simultaneously determines choorpheniramine, two metabolites (mono- and di-desmethylchlorpheniramine), pseudoephedrine, and norpseudoephedrine. The assay recovery was less than 97% (0.06-3 microgram/ml) for chlorpheniramine maleate and less than 98% (1.5-75 microgram/ml) for pseudoephedrine hydrochloride. Excretion of chlorpheniramine and its two metabolites in urine was enhanced after ammonium chloride administration. At steady state, a change in urine pH from 5.69 to 6.46 resulted in more than a 25% decrease in chlorpheniramine and monodesmethylchlorpheniramine excretion. In spite of expected changes in its biological half-life, the overall amount of unchanged pseudoephedrine excreted in urine was not affected by urine pH, presumably because it is primarily excreted in urine as intact drug.

Chlorpheniramine↗