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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.

The pharmacokinetics of N-acetylprocainamide, administered orally or intravenously, were studied in 3-, 6-, and 12-month-old rats using a two-way crossover study design. At 3, 6, and 12 months of age, the half-life values of N-acetylprocainamide were 1.66, 1.82, and 2.29 hr, respectively; the apparent volumes of distribution were 4.75, 3.35, and 1.98 liter/kg, respectively. The elimination rate constant, clearance, and absolute bioavailability of the drug (determined by AUC measurements and the amounts excreted unchanged in the urine) decreased significantly with age. The rate of absorption remained unchanged. The amounts of N-acetylprocainamide in the liver and kidneys were significantly higher in the 12-month-old animals. These results clearly demonstrate a significant alteration with age in the bioavailability, distribution, and elimination of N-acetylprocainamide in rats. In long-term toxicity studies of this and other drugs that show age-dependent pharmacokinetics, an adjustment in the chronically administered dose is essential.

The purpose of this study was to determine the distribution of N-acetylprocainamide (NAPA) in heart, kidney, and liver tissues of rats and their relationship to the plasma concentration after intravenous administration of the drug (100 mg/kg) to 24 Charles River rats. A specific HPLC procedure was used. The plasma and tissue concentrations of NAPA declined biexponentially in parallel, with an elimination half-life of about 1.8 hr. The equilibrium between plasma and the organs tested in this study was attained within 5 min. The tissue/plasma concentration ratio remained constant throughout the study. The tissue/plasma ratios for heart, kidney, and liver were 2.1, 7.9, and 2.4, respectively. The data indicate that: a) these organs have greater affinity to NAPA than do plasma proteins, and b) plasma concentrations may be reliable measures of the therapeutically effective concentrations at the site of action, i.e., the heart tissues.

Six groups of rats received saline or N-Acetylprocainamide (NAPA) 2--50 mg/kg, intraperitoneally. Thirty minutes later heart rates were measured and simultaneously a blood sample was withdrawn from each rat. There was a linear relationship between plasma concentrations and the administered doses, suggesting linear pharmacokinetics for NAPA. The heart rate was decreased significantly when the average NAPA plasma concentration was 16.8 microgram/ml, which is similar to that found in man.

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%.

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.

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.