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PubMed1989

Chronopharmacokinetic studies of pranoprofen and procainamide.

There is increasing evidence demonstrating that plasma drug concentrations are affected by their time of administration. In the current study, the chronopharmacokinetic profiles of an antipyretic agent, pranoprofen, and an antiarrhythmic agent, procainamide, were examined. In the first study, 75 mg of pranoprofen was given orally in seven healthy subjects at 10:00 (morning trial) or 22:00 (evening trial). In the second study, 500 mg of procainamide was given orally in eight subjects with premature ventricular contractions at 10:00 or 22:00. Blood samples for plasma drug concentrations were taken for a 10-hour (pranoprofen study) or a 24-hour (procainamide study) post-drug period. In the first (pranoprofen) study, the mean time to maximum concentration was significantly shorter, and the mean maximum plasma concentration as well as absorption rate constant had a tendency to be greater after the morning than after the evening trial. The mean area under the plasma concentration-time curve, elimination half-life or oral clearance of the morning and evening dosages did not differ. In the second (procainamide) study, no significant difference was observed in any pharmacokinetic parameter concerning procainamide or its active metabolite, N-acetyl-procainamide (NAPA) between the morning and evening trials. These data indicate that plasma levels of pranoprofen are affected by its administration time while plasma concentrations of procainamide and NAPA do not vary with the time of dosage.

Acecainide↗
PubMed1995

Inhibition of N-acetylation of procainamide and renal clearance of N-acetylprocainamide by para-aminobenzoic acid in humans.

Procainamide administration often results in excessively high serum N-acetylprocainamide (NAPA) concentrations and subtherapeutic serum procainamide concentrations. Inhibition of N-acetylation of procainamide may prevent accumulation of excessive NAPA while maintaining therapeutic serum procainamide concentrations. The purpose of this randomized, two-way crossover study was to determine if para-aminobenzoic acid (PABA) inhibits N-acetylation of procainamide in healthy volunteers. Eleven (7 female, 4 male) fast acetylators of caffeine received, in random order, PABA 1.5 g orally every 6 hours for 5 days, with a single intravenous dose of procainamide 750 mg administered over 30 minutes on the third day, or intravenous procainamide alone. Blood samples were collected during a 48-hour period after initiation of the infusion. Urine was collected over a 72-hour period. Serum procainamide and NAPA concentrations were analyzed using fluorescence polarization immunoassay. Urine procainamide and NAPA concentrations were measured with high performance liquid chromatography. PABA did not significantly influence total or renal procainamide clearance, elimination rate constant, AUC0-00, amount of procainamide excreted unchanged in the urine, or volume of distribution. However, concomitant PABA administration with procainamide resulted in increases in NAPA AUC0-00 and t1/2 and reductions in NAPA Ke, procainamide acetylation (NAPA formation) clearance, and NAPA renal clearance. Although PABA inhibits metabolic conversion of procainamide to NAPA, it also impairs the renal clearance of NAPA (but not procainamide) in healthy subjects. Therefore, PABA may not be useful for optimizing the safety of efficacy of procainamide in patients.

4-Aminobenzoic Acid↗
PubMed1996

Pharmacokinetic and pharmacodynamic comparisons of twice daily and four times daily formulations of procainamide in patients with frequent ventricular premature depolarization.

A study was conducted to evaluate the pharmacokinetics of procainamide and its active metabolite, N-acetylprocainamide (NAPA), as a function of dose and formulation and to characterize the relationship between ventricular premature depolarization (VPD) rate and plasma concentrations of procainamide and NAPA. A subset of patients (n = 43) with frequent VPD who were enrolled in a double-blind, multicenter, activity trial were assigned in randomized fashion to receive 1 of 4 dose levels (placebo or 1,000, 2,000, or 4,000 mg/day procainamide) and to receive Procanbid (Parke-Davis) tablets every 12 hours or Procan SR (Parke-Davis) tablets every 6 hours during the first week of a blinded crossover phase. Patients crossed over to the alternative formulation after one week. Maximum and steady-state average concentrations of procainamide and NAPA after administration of Procanbid tablets were equivalent to those after administration of an equivalent daily dose of Procan SR tablets. Corresponding trough concentrations of procainamide were lower after administration of Procanbid tablets than after administration of Procan SR tablets. Both formulations produced disproportionate increases in procainamide concentrations with increasing dose; concentrations of NAPA increased in proportion to dose. Assessment of the relationship between VPD rate and drug concentration in plasma indicated no substantive difference between the two formulations. It was concluded that administration of Procanbid tablets every 12 hours is essentially equivalent to administration of procainamide extended-release tablets (Procan SR) every 6 hours with respect to pharmacokinetics of procainamide and NAPA and to VPD suppression.

Acecainide↗
PubMedDate not supplied

N-acetylprocainamide kinetics during intravenous infusions and subsequent oral doses in patients with coronary artery disease and ventricular arrhythmias.

The kinetics of N-acetylprocainamide (NAPA) were studied in 5 patients (all men, mean age = 62) with coronary artery disease and ventricular arrhythmias during loading infusions of 0.22-0.45 mg/kg/min, prolonged (19-48 hrs) intravenous infusions 2.5-5.2 mg/min, and in 4 of the patients, during subsequent oral doses 1.5-3 g every 8 hrs. Serum, concentrations of NAPA were determined by high-performance liquid chromatography. The individual concentration-time profiles could, with one exception, be described by a two-compartment, open, kinetic model with apparent first-order elimination. The kinetic variables were: initial distribution volume (Vc) 0.20 +/- 0.11 l/kg (mean +/- SD); steady-state distribution volume (Vss) 1.58 +/- 0.55 l/kg; distributional clearance (Cle) 133 +/- 23 ml/(kg X hr); absorption rate constant (Ka) 0.354 +/- 0.173 hr-1; and fraction of dose reaching systemic circulation (F) 1.00 +/- 0.14. The data for one patient who had received increasing oral dosages of 1.5, 2, 2.5 and 3 g every 8 hours resulted in systematic underprediction of observed concentrations at the two highest oral dosing rates. This suggests the possibility of some degree of nonlinearity or time-dependent change in the kinetic behavior of NAPA. Only low concentrations of procainamide, less than 1 mg/L, were found at the end of the infusions.

Acecainide↗
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↗
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↗
PubMed1983

Age-related pharmacokinetics of N-acetylprocainamide in rats.

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.

Acecainide↗
PubMed1984

Colorimetric determination of procainamide in injectable preparations.

A simple, rapid colorimetric method is described which determines procainamide in commercially available, injectable solutions. It is based on complexing the drug with cupric ion and then measuring the absorption at 380 nm. The reaction is fast and the metal-drug ratio in the complex is 1:1. The pH optimum for maximum reaction is 4.0-4.5 which is maintained by an acetate buffer. Linear standard curves were obtained from 1.52 to 6.06 mg/mL. Analysis of 29 commercial samples resulted in an average of 97.3% of the label claim.

Acecainide↗
PubMed1987

Reversed-phase liquid chromatography method for measurement of procainamide and three metabolites in serum and urine: percent of dose excreted as deethyl metabolites.

We report a reversed-phase high-performance liquid chromatography method for the determination of procainamide (PA) and three of its metabolites, n-acetylprocainamide (NAPA), deethylprocainamide (DEPA), and deethyl-n-acetylprocainamide (DENAPA), in serum and urine. (p-Amino)-n-(2-dipropylaminoethyl)-benzamide was the internal standard. A phenyl column (1.0-mL/min flow rate) and a mobile phase consisting of 0.075 M acetate buffer (pH 4.3):acetonitrile (20:3) resulted in a total chromatography time of 21.6 min. The optimum detector wavelength was 270 nm. Maximum linear concentrations were 37.8, 34.2, 20.0, and 16.3 mg/L for DEPA, DENAPA, PA, and NAPA, respectively. Minimum detectable concentrations were 0.05 mg/L or less for all four compounds. One-tenth milliliter of sample was extracted into methylene chloride:2-propyl alcohol (9:1). Extraction efficiencies were independent of concentration or biological fluid for each compound. Standard curves were linear and best-fit by dividing the curve into two portions and/or using weighted linear regression. Within-day and day-to-day precison were excellent. No interfering substances were observed in the serum or urine of normal subjects with the exception of caffeine, which was resolved by alteration of the mobile phase. Advantages of this method include a small sample volume, low minimum detectable concentrations, and an order of elution which enhances the detectability of the deethyl metabolites. Urinary excretion of DEPA and DENAPA accounted for an average of only 0.58 and 0.53%, respectively, of PA doses administered intravenously to six normal volunteers.

Acecainide↗
PubMed1993

T lymphocytes ignore procainamide, but respond to its reactive metabolites in peritoneal cells: demonstration by the adoptive transfer popliteal lymph node assay.

The drug procainamide (PA) is notorious for causing drug-induced systemic lupus erythematosus (SLE) in humans. Indirect evidence suggests that metabolism of PA to a reactive intermediate metabolite is involved in the pathogenesis of drug-induced SLE in that N-hydroxylation of the arylamine group of PA favors this condition, whereas N-acetylation prevents it. If this is correct, one would expect hydroxylamine-PA (HAPA) to be immunogenic, whereas N-acetyl-PA (N-ac-PA) should be nonimmunogenic. This hypothesis was confirmed by means of the popliteal lymph node assay (PLNA) in mice: injection of PA and N-ac-PA failed to induce a reaction in the direct PLNA, whereas HAPA induced a vigorous reaction. Using the adoptive transfer PLNA, splenic T cells of mice that had received three injections of HAPA were shown to be specifically sensitized to this metabolite, but not to PA or N-ac-PA. In this system, an anamnestic T cell response could also be elicited when homogenized peritoneal cells of mice that had been treated with PA for 4 months were used as the challenging antigen, indicating that the peritoneal cells of PA-treated animals contained or had been exposed to the reactive intermediate metabolite HAPA. Whereas in slow acetylator mice this 4-month PA treatment sufficed to generate HAPA in peritoneal cells, fast acetylators required additional stimulation of their oxidative metabolism in order to produce enough HAPA detectable by sensitized T cells. These findings clearly support the concept that reactive intermediate metabolites, such as HAPA, are generated by the oxidative metabolism of phagocytic cells and are immunogenic for T cells.

Acecainide↗
PubMed1983

Significance of acetylator phenotype in pharmacokinetics and adverse effects of procainamide.

The pharmacokinetics and development of antinuclear antibodies (ANAs) during procainamide (PA) therapy were studied in 35 patients with ventricular arrhythmias. Sixteen of the subjects were rapid and 19 were slow acetylators. Twenty-six of them (13 rapid and 13 slow acetylators) received PA therapy (2.4g sustained-release PA X HCl daily in three doses) for at least 16 weeks. On maintenance therapy, rapid acetylators had insignificantly lower serum PA concentrations and slightly higher N-acetylprocainamide (NAPA) concentrations than slow acetylators. The unchanged PA fraction (PA/PA + NAPA) in the rapid acetylators was somewhat lower than in the slow acetylators. Rapid acetylators excreted more NAPA in urine than did slow acetylators (p less than 0.05), whereas the difference in PA excretion was not significant. More than 80% of the given drug was excreted as PA and NAPA. Spontaneous or exercise-induced arrhythmias were recorded in 6 rapid and 8 slow acetylators. ANAs (titre at least 20) appeared in 6 rapid and 8 slow acetylators. The mean time until ANA development in rapid acetylators was only marginally longer than in slow acetylators. The results suggest that acetylation phenotyping is not of great significance in predicting the development of ANAs during PA therapy.

Acecainide↗
PubMed1983

Cimetidine-procainamide pharmacokinetic interaction in man: evidence of competition for tubular secretion of basic drugs.

The hypothesis that basic drugs can compete for active tubular secretion by the kidney was tested in six healthy volunteers by comparing the single dose pharmacokinetics of oral procainamide before and during a daily dose of cimetidine. The area under the procainamide plasma concentration-time curve was increased by cimetidine by an average of 35% from 27.0 +/- 0.3 micrograms/ml X h to 36.5 +/- 3.4 micrograms/ml X h. The elimination half-life increased from an harmonic mean of 2.92 to 3.68 h. The renal clearance of procainamide was reduced by cimetidine from 347 +/- 46 ml/min to 196 +/- 11 ml/min. All these results were statistically significant (p less than 0.016). The area under the plasma concentration-time curve for n-acetylprocainamide was increased by a mean of 25% by cimetidine due to a significant (p less than 0.016) reduction in renal clearance from 258 +/- 60 ml/min to 197 +/- 59 ml/min. The data suggests that cimetidine inhibits the tubular secretion of both procainamide and n-acetylprocainamide, and, if so, represents the first documented evidence for this type of drug interaction in man. The clinical implications from this study necessitate dosage adjustments of procainamide in patients being concomitantly treated with cimetidine. The interaction is pertinent not only for basic drugs that are cleared by the kidney, but also for metabolites of basic drugs and endogenous substances which require active transport into the lumen of the proximal tubule of the kidney for their elimination.

Absorption↗
PubMed1989

Oral N-acetylprocainamide compared to quinidine plus digoxin in the chronic suppression of atrial flutter in humans.

Antiarrhythmic therapy for the suppression of atrial flutter has conventionally entailed the use of a class Ia agent such as quinidine or procainamide. However, atrial flutter often recurs despite the use of these conventional antiarrhythmic regimens. Experimental and clinical evidence suggests that the pharmacologic suppression of atrial flutter may depend on the prolongation of the atrial action potential duration and consequently the voltage-dependent refractoriness. Therefore, the efficacy and tolerance of the class III antiarrhythmic agent N-acetylprocainamide was compared to that of the conventional regimen of the class Ia agent quinidine combined with digoxin (to control ventricular response) in patients with a history of symptomatic sustained atrial flutter. The study was randomized but nonblinded, with a crossover to the alternate regimen if the first failed. Eighteen patients entered the study and were followed for up to 18 months. Of the 12 receiving N-acetylprocainamide (eight randomized and four crossovers), one (8%) failed therapy due to side effects, but none had atrial flutter. Of the 11 receiving quinidine and digoxin (10 randomized and one crossover), three (28%) had a recurrence of atrial flutter, two of whom also had intolerable side effects, and two more (18%) had side effects alone requiring withdrawal of therapy (total 46% failed). The probability of therapeutic success over time was greater (p less than 0.04) for N-acetylprocainamide than for quinidine and digoxin. The data suggest that N-acetylprocainamide may be more effective and better tolerated than the conventional regimen of quinidine plus digoxin. Therefore, large-scale blinded studies of the efficacy of N-acetylprocainamide in the suppression of atrial flutter may be warranted.

Acecainide↗
PubMed1982

Selection of an antiarrhythmic drug for a sudden-death-prevention trial.

Several therapeutic approaches have sought to prevent the occurrence of sudden cardiac death. Many sudden deaths are presumed to be due to an arrhythmia, but the drugs best known for antiarrhythmic activity, the local anesthetic agents, have not been suitable prophylactic agents because of their toxicities and other undesirable pharmacologic characteristics. Several new drugs in this class have been synthesized and are currently being tested for antiarrhythmic activity in clinical trials. One of them may prove to be worthy of a large-scale clinical trial to determine whether chronic arrhythmia suppression reduces the risk of sudden death. The characteristics of the "ideal" antiarrhythmic agent are discussed, and a brief summary of the drugs currently being tested in the United States is presented. The discussion of each drug emphasizes the characteristics that might make it suitable--or unsuitable--for use in a sudden-death trial. Many agents being tested are clearly not satisfactory for such a trial. However, they may be prototypes for an ideal drug or combination of drugs that might yet be developed.

Acecainide↗
PubMed1983

Electrophysiologic properties and antiarrhythmic mechanisms of intravenous N-acetylprocainamide in patients with ventricular dysrhythmias.

To define electrophysiologic properties and antiarrhythmic mechanisms of N-acetylprocainamide (NAPA), we studied 16 patients with symptomatic ventricular dysrhythmias. Electrophysiologic studies were performed before and after intravenous infusion of NAPA at 20 mg/kg over 20 minutes, achieving plasma concentrations of 24 +/- 3.2 to 35.5 +/- 4.5 micrograms/ml. NAPA did not significantly change sinus cycle length or atrioventricular (AV) conduction times (PA, AH, HV, and QRS), but it lengthened the QTc interval (p less than 0.001) during sinus rhythm. Programmed atrial stimulation revealed that NAPA had no discernible effects on AV nodal conduction; however, it exerted depressive effects on the His-Purkinje system in 9 of 16 patients. In 7 of 16 patients who manifested frequent ventricular premature beats (VPBs), NAPA abolished VPBs in only three of them; NAPA induced progressive prolongation of the premature coupling interval before complete abolition of VPBs. In 8 of 16 patients who had inducible repetitive ventricular response (RVR) because of reentry within the His-Purkinje system, NAPA narrowed or abolished the RVR zone in 3 patients and slowed the RVR rate with widening of the RVR zone in the remaining 5 patients. In 2 of 16 patients with slow ventricular tachycardia (VT), NAPA had no antiarrhythmic effects. By contrast, in the other 2 of 16 patients in whom sustained VT could be reproducibly elicited with programmed ventricular stimulation, NAPA slowed the rate of VT and suppressed VT inducibility. We conclude that electrophysiologic properties of NAPA are slightly different from those of procainamide and that NAPA is not uniformly effective for suppressing ventricular dysrhythmias, but its antiarrhythmic mechanisms are similar to those of procainamide.

Acecainide↗