Drug-herb interaction: effect of St John's wort on bioavailability and metabolism of procainamide in mice.

CONTEXT: St John's wort induces the activity of the cytochrome P450 enzyme system causing treatment failure because of increased metabolism of many drugs. Procainamide is metabolized by a different pathway to N-acetyl procainamide. OBJECTIVE: To study St John's wort-procainamide interaction using a mouse (Swiss Webster) model. DESIGN: One group of mice (group A, 4 mice in each group) was fed St John's wort each day for 2 weeks (last dose 1 day before administration of procainamide); another group (group B) received the same dose of St John's wort for 1 week. The third group (group C) received only a single dose 1 hour before administration of procainamide, and the control group (group D) received no St John's wort. All groups later received a single oral dose of procainamide. Blood was drawn 1, 4, and 24 hours after administration of procainamide and concentrations in serum of procainamide as well as N-acetyl procainamide were measured using immunoassays. RESULTS: The procainamide concentrations 1 hour after administration was highest in group C (mean, 11.59 microg/mL) followed by group A (9.92 microg/mL), whereas group B (7.44 microg/mL) and control group D (7.36 microg/mL) showed comparable values. The concentration in group C was significantly greater than the control group D (P = .03, 2-tailed independent t test). N-Acetyl procainamide concentrations and estimated half-life of procainamide among groups were comparable. In a separate experiment when mice were fed purified hypericin, the active component of St John's wort, a significant increase in bioavailability (53%) of procainamide was observed compared with the control group. CONCLUSIONS: St John's wort has an acute effect to increase bioavailability of procainamide but has no effect on its metabolism.

Application of a generic physiologically based pharmacokinetic model to the estimation of xenobiotic levels in human plasma.

Estimation of xenobiotic kinetics in humans frequently relies upon extrapolation from experimental data generated in animals. In an accompanying paper, we have presented a unique, generic, physiologically based pharmacokinetic model and described its application to the prediction of rat plasma pharmacokinetics from in vitro data alone. Here we demonstrate the application of the same model, parameterized for human physiology, to the estimation of plasma pharmacokinetics in humans and report a comparative evaluation against some recently published predictive methods that involve scaling from in vivo animal data. The model was parameterized through an optimization process, using a training set of in vivo data taken from the literature, and validated using a separate test set of published in vivo data. On average, the vertical divergence of the predicted plasma concentrations from the observed data, on a semilog concentration-time plot, was 0.47 log unit. For the training set, more than 80% of the predicted values of a standardized measure of the area under the concentration-time curve were within 3-fold of the observed values; over 70% of the test set predictions were within the same margin. Furthermore, in terms of predicting human clearance for the test set, the model was found to match or exceed the performance of three published interspecies scaling methods, all of which showed a distinct bias toward overprediction. We conclude that the generic physiologically based pharmacokinetic model, as a means of integrating readily determined in vitro and/or in silico data, is potentially a powerful, cost-effective tool for predicting human xenobiotic kinetics in drug discovery and risk assessment.

Levofloxacin and ciprofloxacin decrease procainamide and N-acetylprocainamide renal clearances.

Ten healthy adults participated in a randomized, crossover drug interaction study testing procainamide only, procainamide plus levofloxacin, and procainamide plus ciprofloxacin. During levofloxacin therapy, most procainamide and N-acetylprocainamide (NAPA) pharmacokinetic parameters, including decreased renal clearances and renal clearance/creatinine clearance ratios, changed (P < 0.05). During ciprofloxacin treatment, only procainamide and NAPA renal clearances decreased significantly.

Quantitative estimation of renal clearance of N-acetylprocainamide in rats with various experimental acute renal failure.

The dosage regimen of a drug eliminated predominantly through the kidney need to be adjusted for the patients with renal disease. The objective of the present study was to establish a quantitative approach to precisely predicting the renal clearances of basic drugs using N-1-methylnicotinamide (NMN). A variety of experimental acute renal failure (ARF) in rats were prepared and N-acetylprocainamide (NAPA) was used as a model drug. The renal clearances of NAPA were significantly decreased in rats with ARF, resulting in significantly increased plasma concentrations. Remarkable reduction in clearance ratios (CL(ratio)) was observed, indicating that the impairment in tubular and glomerular function did not proceed in a parallel manner. The renal clearance of NAPA (CL(rNAPA)) was better predicted from the renal clearance of NMN (CL(rNMN)) than from GFR. A mathematical equation was also constructed to estimate the CL(rNMN) from the NMN plasma concentration. Therefore, the renal clearance of basic drugs excreted predominantly from the kidney can be easily and more accurately estimated based on the concentrations of endogenous NMN to provide a precise dosage regimen for patients with renal failure.

The influence of moderate and chronic exercise training on the pharmacokinetics of procainamide and N-acetylprocainamide.

The effect of moderate and prolonged exercise on the disposition and metabolism of drugs has not been extensively examined. The present study examined the effect of exercise training on the pharmacokinetics of procainamide and its active metabolite, N-acetylprocainamide. Male Sprague Dawley rats were randomly assigned to three testing groups: (1) sedentary, (2) 4 weeks of exercise training and (3) 8 weeks of exercise training. Treadmill speed and exercise duration were gradually increased, reaching a final rate of 24 m min-1 for an hour by the end of the 4-week or 8-week period. Sedentary and exercise trained rats received a single i.p. dose of procainamide (100 mg kg-1). Serial blood samples were collected over a 10 h period and plasma samples were analysed by an UV-HPLC method. Noncompartmental analysis was performed to estimate the pharmacokinetic parameters. The t1/2 of procainamide was significantly (p < 0.05) higher in the 8 week exercise group (331 min) as compared to the sedentary group (77 min). In addition, there was a significant reduction in the amount of N-acetylprocainamide formed after 8 weeks of exercise (AUCNAPA = 739 ng mL-1 min-1). Results of this study suggest that prolonged exercise (8 weeks of training) alters the pharmacokinetics of procainamide by modifying the amount of active metabolite formed.

Effect of age, gender, and race on steady state procainamide pharmacokinetics after administration of procanbid sustained-release tablets.

Procainamide hydrochloride is a Class 1A antiarrhythmic agent administered intravenously or orally for treatment of symptomatic ventricular premature depolarizations (VPD), nonsustained ventricular tachycardia, and life-threatening ventricular arrhythmias. A new sustained-release formulation, Procanbid, which allows for twice-daily dosing was recently approved for marketing in the United States. This paper describes the population pharmacokinetics of procainamide and N-acetylprocainamide (NAPA), the major metabolite, in healthy volunteers and patients with VPD by combining Cmax, tmax, Cmin, and AUC(0-12) values at steady state from six multiple-dose studies in which one 1000-mg or two 500-mg Procanbid tablets were administered. Means of parameters by race and gender were inspected for trends likely to be of clinical relevance. Procainamide and NAPA pharmacokinetic parameters observed after administration of Procanbid tablets were similar in blacks and whites, and in men and women. However, differences in body size should be considered when determining the Procanbid dose for women. Participant age had significant impact on NAPA pharmacokinetics in this study population and should be considered in dose selection. Age effects on procainamide were not detected in the study population, which was heavily weighted toward younger subjects, but are anticipated in the older population of patients for which procainamide is indicated. Procanbid formulation performance was not altered by patient demographics.

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.

Application of computer-assisted radiotelemetry in the pharmacokinetic and pharmacodynamic modeling of procainamide and N-acetylprocainamide.

The cardiovascular pharmacodynamics (PD) of procainamide and N-acetylprocainamide have not been well characterized in small rodents without the presence of anesthesia or restraint. This study was undertaken to examine the pharmacokinetics (PK) and PD relationship of procainamide and N-acetylprocainamide by use of electrocardiogram (ECG) telemetry in unrestrained rats. Male Sprague Dawley rats received the following treatments: vehicle, procainamide 50 and 100 mg/kg and N-acetylprocainamide 50 and 100 mg/kg via intraperitoneal (i.p.) administration. Blood samples were collected over 8 h and subsequently analyzed. PD measurements (PQ, QS, QR, QT, RR, and HR) were collected prior to dosing and over a 24 h period. Mean PK parameters after the 50 mg/kg dose were as follows: Cls/Fprocainamide = 86.42 mL min-1 kg-1, Cls/FN-acetylprocainamide = 36.62 mL min-1 kg-1, Vdprocainamide = 10.42 L/kg, and VdN-acetylprocainamide = 5.91 L/kg. The relationship between concentration (procainamide or N-acetylprocainamide) and effect (percent change QT interval) was best described by an Emax model for procainamide (EC50 = 445 ng/mL; Emax = 30.09%). These results approximate ECG changes noted in procainamide clinical studies, suggesting that telemetry can be used as a predictive tool of efficacy. Furthermore, the proposed PK-PD model describes the electrophysiological effects associated with procainamide.

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.

The influence of selected general anesthetics on pharmacokinetic parameters of some antiarrhythmic drugs in rabbits. Part II. N-acetylprocainamide.

The influence of general anesthesia with thiopental (10 mg/kg), ketamine (4 mg/kg), propofol (10 mg/kg) or pentobarbital (20 mg/kg) on the N-acetylprocainamide (15 mg/kg) pharmacokinetic parameters was studied in rabbits. It was established that during thiopental or pentobarbital anesthesia the levels of N-acetylprocainamide may be temporary higher than therapeutic levels. The following main changes in N-acetylprocainamide pharmacokinetic parameters were found: 1) increase of the elimination rate and shortening of biological half-life during thiopental or ketamine anesthesia 2) decrease of mean residence time during thiopental anesthesia 3) increase of the elimination rate from the central compartment constant (but not the mean residence time) during pentobarbital anesthesia 4) decrease of distribution rate and penetration rates (k12, k21) during propofol anesthesia.

The influence of selected general anesthetics on pharmacokinetic parameters of some antiarrhythmic drugs in rabbits. Part I. Procainamide and its active metabolite-N-acetylprocainamide.

The influence of general anesthesia with thiopental (10 mg/kg), ketamine (4 mg/kg), propofol (10 mg/kg) or pentobarbital (20 mg/kg) on the pharmacokinetics of procainamide (13 mg/kg) and its active metabolite-N-acetylprocainamide was studied in rabbits. The general anesthesia with those drugs caused only the slight changes in procainamide pharmacokinetics, namely changing volume of distribution, penetration rate constants between central and peripheral compartments. However, the following main changes in N-acetylprocainamide (metabolite) pharmacokinetic parameters were found: 1) increase of the penetration rate constants between the compartments and mean residence time during propofol anesthesia 2) prolongation of the mean residence time during thiopental anesthesia 3) increase of mean residence time of N-acetylprocainamide during anesthesia with ketamine, pentobarbital or propofol.

Prediction of N-acetylprocainamide disposition kinetics in rat by combination of gamma variate and physiological pharmacokinetic model.

Clearances and tissue/blood drug concentration ratios of N-acetylprocainamide (NAPA) in rats were determined. The clearances of NAPA in rat blood, liver, and kidney were 13.1, 4.88, and 8.24 ml.kg-1.min-1, respectively. Disposition kinetics of NAPA in rats was predicted with combination of gamma variate and physiological pharmacokinetic model. Equation for estimating the concentration of NAPA in rat blood following iv NAPA 40 mg.kg-1 was C = 55.06t(-0.220) exp(-0.00713t). Using r2 value as a criterion, we found a good agreement between predicted and observed concentrations in blood, lung, small intestine, heart, brain, and skin.

Propylene glycol as a vehicle for percutaneous absorption of therapeutic agents.

Propylene glycol (PG) was evaluated as a vehicle for the in vivo percutaneous absorption of the hydrochloride salts of desipramine, nortriptyline, procainamide, and N-acetyl-procainamide. Each drug was administered topically to hairless (hr-1/hr-1) mice in water and in aqueous 10% and 50% PG. Mean drug concentrations in blood, brain, heart, liver, and lung were measured by high-pressure liquid chromatography after either two or three hours of topical absorption. The presence of PG generally enhanced the absorption of each drug, and the degree of enhancement appeared to be related to the percentage of PG in the dosing solution.

Acecainide pharmacokinetics in normal subjects of known acetylator phenotype.

The purpose of this study was to determine the pharmacokinetics of acecainide (formerly N-acetylprocainamide) in six normal subjects of known acetylator phenotype. Three subjects were fast acetylators and three slow acetylators by sulfapyridine phenotyping criteria. Each subject received a 20-min, 3 mg kg-1 intravenous acecainide infusion. Concentrations of acecainide, procainamide, and their deethylated metabolites were measured in serum and urine samples using HPLC. Acecainide renal clearance, nonrenal clearance, steady-state volume of distribution, and other pharmacokinetic parameters were estimated using standard approaches. Acecainide renal clearance and steady-state volume of distribution were (mean +/- SD) 13.6 +/- 1.581 h-1 and 135 +/- 20.31, respectively, and were not significantly different in fast and slow acetylators. Acecainide nonrenal clearance in the six subjects was 3.0 +/- 1.01 h-1; however, nonrenal clearance in slow acetylators was 1.8 times that in fast acetylators (3.9 vs 2.21 h-1, p = 0.012) with clear separation of the subjects into two groups when the data were grouped by acetylator phenotype. The nonrenal clearance of acecainide was inversely correlated with percentage sulfapyridine acetylation. Computer simulations were conducted to explore possible explanations for the observed difference in nonrenal clearance.

[Combined pharmacokinetic and pharmacodynamic model analysis for procainamide and its metabolite].

The pharmacokinetic and pharmacodynamic profiles of procainamide (PA) and its major metabolite, acetylprocainamide (NAPA), were analyzed by extended combined pharmacokinetic and pharmacodynamic model in rabbits. The pharmacodynamic parameters Keo, S, Ce(50), Emax for PA were 0.023 +/- 0.005 min-1, 3.9 +/- 1.1, 3.6 +/- 0.9 micrograms.ml-1, 37 +/- 10 ms respectively and for NAPA were 0.061 +/- 0.017 min-1, 2.2 +/- 0.4, 6.2 +/- 1.7 micrograms.ml-1, 53.6 +/- 2.5 ms. Following PA iv to rabbit both PA and NAPA were involved in the QTc prolongation of the initial period, but the later action was mainly associated with NAPA. Differences of pharmacokinetic and pharmacodynamic parameters between PA and NAPA were found.

[Combined pharmacokinetic-pharmacodynamic model of procainamide in rabbits with induced ventricular fibrillation threshold (VFT) changes].

The change of electrically induced VFT was chosen as index of effect in anesthetized rabbits for study of pharmacodynamics of PA and NAPA. We analyzed the pharmacokinetic properties of PA and NAPA and elucidated their effect kinetics with a pharmacokinetic-pharmacodynamic (PK/PD) model in view of different transfer qualities. A linear-addition effect model was used to describe the relationship between the effect and the amount of drug and its metabolite in the effect compartment. PA was found to be eliminated faster than NAPA and distributed more extensively in rabbits. The effect per unit concentration of PA was shown to be larger than that of NAPA.

Comparison of transport of procainamide and N-acetylprocainamide from blood into the intestinal lumen with that into the peritoneal cavity in rats.

Transfer of procainamide and its active metabolite, N-acetylprocainamide (NAPA) from the blood into the intestinal lumen was compared with that into the peritoneal cavity after i.v. administration of procainamide at the dose of 10 mg/kg to rats. The amounts of both drugs transferred from the blood into the intestinal lumen were much greater than those into the peritoneal cavity. The average amounts of procainamide transferred in 2 h into the intestinal lumen and the peritoneal cavity were 12.7% and 1.7% of dose (10 mg/kg), respectively, while those of NAPA were 3.5% and 1.4% of dose. The intestinal and peritoneal clearance values of procainamide were 143.5 and 59.4 ml/h, respectively, and those of NAPA were 32.6 and 13.5 ml/h. The difference in transfer rates across the intestinal and peritoneal membranes may be due to difference in the area of permeative surface and the extent of ionization in the dialysate. Consequently, it is expected that the gastrointestinal dialysis by oral administration of activated charcoal may serve as one of the more useful hemopurification methods than the peritoneal dialysis in procainamide and NAPA intoxication.

[Verification of therapeutic levels of procainamide and N-acetyl- procainamide in ventricular arrhythmia]. / Weryfikacja zakresu stezen terapeutycznych prokainamidu i N-acetyloprokainamidu w komorowych zaburzeniach rytmu serca.

Therapeutical efficacy was clinically evaluated in 21 patients with ventricular cardiac arrhythmias. The drug was given orally with preceded intramuscular dose. Therapeutic effect was verified by the measurements of procainamide and N-acetylprocainamide concentrations in blood serum to determine the minimal effective concentration of the drug required to obtain satisfactory antiarrhythmic effect. Procainamide proved effective in cardiac arrhythmias in 14 patients (66.7%) with statistical significance in the acute myocardial infarctions; blood serum procainamide plus N-acetylprocainamide levels being were below the therapeutical range. The poor correlation of the dose of the drug and respective procainamide, N-acetylprocainamide concentrations in blood was observed. Relationship of the therapeutical effects blood serum level of the drug should be estimated basing of the assays of both procainamide and N-acetylprocainamide .