Membrane transport mechanisms of quinidine and procainamide in renal LLC-PK1 and intestinal LS180 cells.

The aim of the present study was to compare the membrane transport mechanisms of procainamide with those of quinidine using renal epithelial LLC-PK(1) and intestinal epithelial LS180 cells. In LLC-PK(1) cells, the transcellular transport of 10 microM quinidine in the basolateral-to-apical direction was similar to that in the opposite direction, and 1 mM tetraethylammonium (TEA) did not affect the transcellular transport of the drug. On the other hand, the transcellular transport of 10 microM TEA and procainamide in LLC-PK(1) cells was directional from the basolateral side to the apical side. In addition, this directional transcellular transport of procainamide was diminished in the presence of 1 mM TEA. In LS180 cells, the temperature-dependent cellular uptake of 100 microM quinidine and procainamide was markedly increased by alkalization of the apical medium, and was inhibited significantly by 1 mM several hydrophobic cationic drugs, but not by TEA. The rank order of the inhibitory effects of hydrophobic cationic drugs on the uptake of procainamide in LS180 cells was imipramine>quinidine>diphenhydramine asymptotically equal topyrilamine>procainamide, which was consistent with that on the uptake of quinidine. These findings suggested that procainamide (but not quinidine) was transported by cation transport systems in renal epithelial cells, but that both procainamide and quinidine were taken up by another cation transport system in intestinal epithelial cells.

Pharmacokinetic evaluation of a sustained-release compounded procainamide preparation after 24-h (acute) administration in normal dogs.

INTRODUCTION: The objective of the present study was to evaluate the pharmacokinetics of a compounded sustained-release procainamide formulation in normal dogs. ANIMALS: Six healthy, purpose-bred mixed-breed dogs participated in the study. METHODS: In phase I, two dogs were administered oral procainamide (30 mg/kg), and plasma was obtained to determine plasma concentration ranges and duration. In phase II, six dogs were administered procainamide (30 mg/kg by mouth every 12 hours) to determine the pharmacokinetics of sustained-release procainamide. Serum procainamide concentration was determined using an immunochemistry assay. RESULTS: No adverse clinical effects were noted in any of the dogs studied. The average maximum serum concentration, average serum concentration, and average minimum serum concentration were 10.17, 7.13, and 3.07 µg/mL, respectively. The average time over a 12-h period during which procainamide concentration exceeded 12 µg/mL was 2.35 h, was between 4 and 12 µg/mL was 7.19 h, and was less than 4 µg/mL was 2.46 h. The average times at maximum concentration and minimum concentration were 18.67 and 12.25 h, respectively. CONCLUSIONS: Administration of sustained-release procainamide twice daily achieved targeted plasma concentrations in most dogs. Evaluation of serum trough concentrations should be considered owing to interanimal variability to confirm that serum concentrations are within the reported therapeutic range for an individual patient.

Therapeutic levels of intravenous procainamide in neonates: a retrospective assessment.

STUDY OBJECTIVES: To evaluate dosing and pharmacokinetic parameters of intravenous continuous-infusion procainamide in neonates, and to identify dosage regimens and factors leading to therapeutic procainamide levels and minimal adverse events. DESIGN: Retrospective, observational study. SETTING: Pediatric hospital. PATIENTS: . Twenty-one patients (seven preterm, 14 full term) younger than 30 days who received continuous-infusion procainamide therapy for more than 15 hours or had two consecutive therapeutic procainamide levels obtained while receiving therapy between June 1, 2002, and December 31, 2005. MEASUREMENTS AND MAIN RESULTS: Data on demographics, dosing, drug levels, and adverse effects were collected. Doses that achieved therapeutic levels were documented, and procainamide clearance was calculated and evaluated with regard to renal function and gestational age in patients who were at steady state. Mean clearance and mean N-acetylprocainamide (NAPA):procainamide ratios were compared between preterm and term neonates. No patients experienced hemodynamic instability or other adverse effects due to procainamide. Procainamide was given as a mean +/- SD 9.6 +/- 1.5-mg/kg bolus in 20 of 21 patients before continuous infusion. The mean +/- SD dose at which two therapeutic levels were achieved was 37.56 +/- 13.52 microg/kg/minute. Procainamide clearance was 6.36 +/- 8.85 ml/kg/minute and correlated with creatinine clearance (r=0.78, p<0.00001) and age at day of sampling (r=0.49, p<0.00001). The NAPA:procainamide ratio at steady state was 0.84 +/- 0.53; two patients were determined to be fast acetylators (ratio > 1). Preterm infants had lower mean clearance rates (p<0.001) but higher NAPA:procainamide ratios (p<0.01) than those of term infants. Five patients experienced seven supratherapeutic levels while receiving therapy; four of these patients were preterm, and all had creatinine clearances less than 30 ml/minute/1.73 m(2). Three patients had four pairs of levels obtained after discontinuation of procainamide, and elimination rate constant and half-life were calculated. CONCLUSION: Procainamide can be safely used in neonates, with no short-term adverse effects. The dosage regimen for intravenous procainamide required to achieve therapeutic levels in neonates is similar to that of older infants and children. Doses may need to be reduced in premature infants and in those with renal dysfunction.

Uptake of the noncytotoxic transport probe procainamide in the Chinese hamster ovary model of multidrug resistance.

Many of the cytotoxic substrates of the multidrug transporter are organic cations. Cimetidine, procainamide, and tetraethylammonium bromide were used in a Chinese hamster ovary model of multidrug resistance, to study handling of noncytotoxic cationic transport probes. Cimetidine and procainamide, but not tetraethylammonium, accumulated to a greater extent (5-fold) in the sensitive CHOAUXB1 (AB) cell line than in the resistant CHRC5 (C5) cell line. Accumulation of both cimetidine and procainamide was significantly increased by verapamil in C5 but not AB. Procainamide accumulation in both AB and C5 was temperature dependent and occurred by passive diffusion. Diltiazem, nifedipine, rifampin, tamoxifen, rhodamine, and ethidium also increased procainamide accumulation in C5 but not AB. Azide in glucose-free medium increased procainamide accumulation in C5, and this was reversed when glucose, but not 3-O-methylglucose, was added. Procainamide efflux rates were similar in AB and C5 and not affected by verapamil or azide. The initial rate of procainamide uptake was higher in AB than in C5, and both verapamil and azide increased the initial rate of procainamide uptake in C5. Thus, differences in accumulation of the noncytotoxic transport probe procainamide in the colchicine-sensitive and colchicine-resistant components of the Chinese hamster ovary cell line mimic the accumulation of known cytotoxic substrates for the multidrug transporter, such as colchicine, vinblastine, and doxorubicin. The differential accumulation of procainamide is due to differences in rates of drug influx, rather than efflux. Since procainamide influx is passive and decreased accumulation in the resistant line appears to parallel M(r) 170,000 glycoprotein presence and activity, we would speculate that decreased procainamide accumulation may be due to an indirect effect of the M(r) 170,000 glycoprotein, such as its effect on intracellular pH.

Hemodynamic effects of intravenous sematilide in patients with congestive heart failure: a class III antiarrhythmic agent without cardiodepressant effects.

OBJECTIVES: This study sought to evaluate the hemodynamic effects of intravenous sematilide hydrochloride, a selective class III antiarrhythmic agent, in patients with heart failure and left ventricular systolic dysfunction. BACKGROUND: Class I antiarrhythmic agents, which primarily slow conduction, can depress ventricular function, particularly in patients with heart failure. In contrast, pure class III agents, which selectively prolong repolarization, do not adversely affect hemodynamic variables in animal models, but there are no data evaluating their hemodynamic effects in humans. METHODS: In 39 patients with congestive heart failure and a left ventricular ejection fraction < 40%, hemodynamic and electrocardiographic measurements were obtained at baseline, after a loading dose and during a maintenance infusion of intravenous sematilide using either a low (0.75 then 0.3 mg/min) or high dose (1.5 then 0.6 mg/min) regimen. The study had an 80% power to detect clinically meaningful differences in hemodynamic variables. RESULTS: Both low (n = 20) and high (n = 19) dose sematilide infusions produced dose-dependent increases in QT interval (5 +/- 8% [mean +/- SD] and 18 +/- 10%, respectively) and corrected QT interval (4 +/- 8% and 14 +/- 10%), and high dose sematilide decreased heart rate by 7 +/- 10% (all p < 0.025 vs. baseline). Neither dose regimen had a statistically significant effect on any other hemodynamic variable, including mean arterial, right atrial, pulmonary artery and pulmonary capillary wedge pressures; cardiac index, stroke volume, systemic and pulmonary vascular resistances; and left ventricular stroke work index. Sematilide showed no adverse hemodynamic effects in patients with left ventricular ejection fraction < or = 25% or > 25% and in patients with cardiac index < 2 or > or = 2 liters/min per m2. Sustained polymorphic ventricular tachycardia (n = 1) and excessive QT prolongation (n = 4) were seen during the high dose. CONCLUSIONS: Sematilide, in the doses administered, prolonged repolarization but did not alter hemodynamic variables in patients with heart failure. These data suggest that class III antiarrhythmic agents, which selectively prolong repolarization, are not cardiodepressant but may be proarrhythmic in humans, especially at high doses.

Trimethoprim inhibition of the renal clearance of procainamide and N-acetylprocainamide.

To test the effect of trimethoprim (an antibiotic commonly administered with sulfamethoxazole) on the disposition of the antiarrhythmic procainamide hydrochloride and its active metabolite N-acetylprocainamide, 10 healthy men received 1 g of procainamide hydrochloride orally on two occasions, coadministered with placebo or trimethoprim (100 mg twice a day for 2 days before and then 200 mg with the procainamide dose). Trimethoprim decreased the mean (+/- SD) renal clearance by 45% after the dose of procainamide was administered (487 +/- 129 vs 267 +/- 123 mL/min) and that of N-acetylprocainamide by 26% (275 +/- 78 vs 192 +/- 82 mL/min) compared with placebo. The mean area under plasma concentration--time curve 0 to 12 hours after dosing increased 39% for procainamide (19.8 +/- 4.8 vs 27.6 +/- 7.2 mg.h/L) and 27% for N-acetylprocainamide (9.1 +/- 2.1 vs 11.4 +/- 2.8 mg.h/L). The corrected QT electrocardiographic interval at 2 hours after the procainamide dose was 0.40 +/- 0.02 second with placebo and 0.43 +/- 0.03 second with trimethoprim. Trimethoprim may increase procainamide and N-acetylprocainamide plasma concentrations, resulting in increased pharmacodynamic response apparently caused by the competition for renal tubular cationic secretion.

Role of CYP2D6 in the N-hydroxylation of procainamide.

Sequential oxidations at the arylamine moiety of the procainamide molecule leading to the formation of N-hydroxyprocainamide and its nitroso derivative may be responsible for lupus erythematosus observed in patients treated with the drug. The objective of the present study was to characterize major cytochrome P450 isozyme(s) involved in the N-hydroxylation of procainamide. Firstly, incubations were performed with microsomes from either lymphoblastoid cells or yeast transfected with cDNA encoding for specific human cytochrome P450 isozymes. Experiments performed with these enzyme expression systems indicated that the highest formation rate of N-hydroxyprocainamide was observed in the presence of CYP2D6 enriched microsomes. Additional experiments demonstrated that the formation rate of N-hydroxyprocainamide by CYP2D6 enriched microsomes was decreased from 45 +/- 4% to 93 +/- 1% by quinidine at concentrations ranging from 30 nM to 100 microM (all p < 0.05 vs control) and by approximately 75% by antibodies directed against CYP2D6. Secondly, incubations were performed with microsomes prepared from 15 human liver samples. Using this approach, an excellent correlation was observed between the formation rate of N-hydroxyprocainamide and dextromethorphan O-demethylase activity (CYP2D6; r = 0.9305; p < 0.0001). In contrast, no correlation could be established between N-hydroxyprocainamide formation rate and caffeine N3-demethylase (CYP1A2), coumarin 7-hydroxylase (CYP2A6), S-mephenytoin N-demethylase (CYP2B6), tolbutamide methlhydroxylase (CYP2C9), S-mephenytoin 4'-hydroxylase (CYP2C19), chlorzoxazone 6-hydroxylase (CYP2E1), dextromethorphan N-demethylase (CYP3A4), testosterone 6 beta-hydroxylase (CYP3A4/5) or lauric acid 12-hydroxylase (CYP4A11) activities. Furthermore, formation rate of N-hydroxyprocainamide was decreased in a concentration-dependent manner by quinidine (300 nM to 100 microM) and by antibodies directed against CYP2D6 but not by furafylline 20 microM (CYP1A2), ketoconazole 1 microM (CYP3A4), sulfaphenazole 10 microM (CYP2C9) or antibodies directed against CYP1A1/1A2, CYP2C, CYP2A6, CYP2E1 or CYP3A4/3A5. In conclusion, the results obtained in the present study demonstrate that CYP2D6 is the major human cytochrome P450 isozyme involved in the formation of the reactive metabolite of procainamide, namely N-hydroxyprocainamide.

Involvement of CYP2D6 activity in the N-oxidation of procainamide in man.

Occurrence of a lupus-like syndrome in a significant number of patients treated with procainamide has limited the clinical use of this antiarrhythmic drug. In-vitro studies conducted in our laboratory have demonstrated that CYP2D6 is the major cytochrome P450 isozyme involved in the formation of N-hydroxyprocainamide, a metabolite potentially involved in the drug-induced lupus erythematosus syndrome observed with procainamide. In the current study, we evaluated the role of CYP2D6 activity in the in-vivo oxidation of procainamide in man. Nineteen healthy individuals, 13 with high (extensive metabolizers) and six with low (poor metabolizers) CYP2D6 activity, received a single 500 mg oral dose of procainamide hydrochloride on two occasions, once alone (period 1) and once during the concomitant administration of the selective inhibitor quinidine (50 mg four times daily; period 2). Blood and urine samples were collected over 36 h after drug administration of procainamide and analysed for procainamide and its major metabolites (N-acetylprocainamide, desethylprocainamide, N-acetyl-desethylprocainamide, p-aminobenzoic acid and its N-acetylated derivative, and nitroprocainamide). No differences were observed in the oral and renal clearances of procainamide between extensive metabolizers and poor metabolizers during either study period. However, partial metabolic clearance of procainamide to desethylprocainamide was significantly greater in extensive metabolizers than in poor metabolizers during both periods. Most importantly, the urinary excretion of nitroprocainamide during period 1 was measurable in 7/13 extensive metabolizers but in none of the poor metabolizers. During the concomitant administration of quinidine, nitroprocainamide could not be detected in the urine of any individuals tested. Therefore, our results suggest that CYP2D6 is involved in the in-vivo aliphatic amine deethylation and N-oxidation of procainamide at its arylamine function in man. Further studies are needed to demonstrate whether a low CYP2D6 activity, either genetically determined or pharmacologically modulated, could prevent drug-induced lupus erythematosus syndrome observed during chronic therapy with procainamide.

Trimethoprim alters the disposition of procainamide and N-acetylprocainamide.

The steady-state pharmacokinetics and pharmacodynamics of procainamide and its active N-acetyl metabolite (NAPA) were assessed alone and in combination with trimethoprim. Eight healthy men received oral sustained-release procainamide, 500 mg every 6 hours for 3 days, alone and with oral trimethoprim, 200 mg daily for 4 days. Concomitant trimethoprim significantly increased the plasma AUC(0-12) of both procainamide and NAPA (63% and 52%, respectively), with concurrent decreases in their renal clearances (47% and 13%, respectively) and a 39% increase in the mean urinary recovery of NAPA (as percentage of procainamide and NAPA recovery). After trimethoprim coadministration, there was also a trend toward a decrease in the apparent acetylation clearance of procainamide (19%, p = 0.057). The change in procainamide and NAPA renal clearances after trimethoprim coadministration strongly correlated with their baseline renal clearances (r = 0.84 and r = 0.74, respectively, p less than 0.0001). There was small but significant increase in the corrected QT interval with procainamide administration, which increased further with trimethoprim coadministration. We conclude that trimethoprim increases the plasma concentrations of procainamide and NAPA by decreasing their renal clearances and allowing more conversion of procainamide to NAPA.

Genotyping of N-acetylation polymorphism and correlation with procainamide metabolism.

We studied the genotypes of polymorphic N-acetyltransferase (NAT2) in 145 Japanese subjects by the polymerase chain reaction-restriction fragment length polymorphism method. The rapid-type NAT2*4 was expressed at a higher frequency (68.6%) than the slow-type genes with specific point mutations (NAT2*6A, 19.3%; NAT2*7B, 9.7%; NAT2*5B, 2.4%). The frequency of NAT2* genotypes consisted of 44% of a homozygote of NAT2*4, 49% of a heterozygote of NAT2*4 and mutant genes, and 7% of a combination of mutant genes. The metabolic activity for procainamide to N-acetylprocainamide was measured in 11 healthy subjects whose genotype had been determined. Although the acetylation activity substantially varied interindividually, the variability was considerably reduced after classification according to the genotype. The N-acetylprocainamide/procainamide ratio in urinary excretion was 0.60 +/- 0.17 (mean +/- SD) for those with NAT2*4/*4, 0.37 +/- 0.06 for NAT2*4/*6A, 0.40 +/- 0.03 for NAT2*4/*7B, and 0.17 for NAT2*6A/*7B. The results indicated that the NAT2* genotype correlates with acetylation of procainamide.

Electrophysiologic and antiarrhythmic activities of 4-amino-N-[2-(diethylamino)ethyl]-3,5-dimethylbenzamide, a sterically hindered procainamide analogue.

Procainamide is a widely used antiarrhythmic that is fraught with therapeutic limitations such as a short half-life, production of autoimmune antibodies and a lupus-like syndrome, and complex pharmacokinetics. We synthesized the congeners of procainamide possessing one or two methyl substituents ortho to the 4-amino moiety (compounds 4 and 5, respectively), in order to sterically encumber the 4-amino substituent and prevent or diminish the rate of metabolic N-acetylation. Moreover, we anticipated that this structural alteration might eliminate the autoimmune toxicities associated with procainamide. Like procainamide, the two methylated analogues significantly reduced the rate of rise and amplitude of the action potential when studied in isolated canine Purkinje fibers. Whereas procainamide caused no significant change in action potential duration (APD), both methylated congeners significantly reduced APD at 70% and 95% repolarization. Moreover, the dimethylated congener was significantly more efficacious than procainamide in reducing ERP (effective refractory period) and increasing the ERP/APD70. The ability of these compounds to block ouabain-induced arrhythmias was studied in anesthetized dogs. Addition of two methyl groups ortho to the amine produced an increase in potency: The conversion doses for procainamide and the monomethyl and dimethyl congeners were 19.0, 18.3, and 14.3 mg/kg, respectively, following iv administration. After iv administration to rats, procainamide was extensively metabolized to N-acetylprocainamide and displayed a half-life of 0.4 h. In contrast, dimethylprocainamide was not metabolized by N-acetylation, had a half-life of 1.4 h, and provided greater peak plasma concentrations. Thus, addition of methyl substituents ortho to the 4-amino group of procainamide alters the electrophysiological characteristics of the compound, increases its potency against ouabain-induced arrhythmias in vivo, increases its plasma half-life, and prevents N-acetylation.

Survival, proliferation, and functions of porcine hepatocytes encapsulated in coated alginate beads: a step toward a reliable bioartificial liver.

Orthotopic liver transplantation is the most effective treatment for fulminant hepatic failure. As an alternative treatment, an efficient extracorporeal bioartificial liver should contain a large yield of functional hepatocytes with an immunoprotective barrier, for providing temporary adequate metabolic support to allow spontaneous liver regeneration or for acting as a bridge toward transplantation. Survival, proliferation, and functions of porcine hepatocytes were evaluated in primary cultures and after embedding in alginate beads, which were subsequently coated with a membrane made by a transacylation reaction between propylene glycol alginate and human serum albumin. Disruption of total pig livers by collagenase perfusion/recirculation allowed the obtention of up to 10(11) hepatocytes with a viability greater than 95%. Hepatocytes in conventional cultures or embedded in coated alginate beads survived for about 10 days, secreted proteins, particularly albumin, and maintained several phase I and II enzymatic activities, namely ethoxyresorufin-O-deethylase, oxidation of nifedipine to pyridine, phenacetin deethylation to paracetamol, glucuroconjugation of paracetamol, and N-acetylation of procainamide. Typical features of mitosis and [3H]thymidine incorporation indicated that porcine hepatocytes proliferated in both conventional cultures and alginate beads. The efficacy of the membrane surrounding alginate beads for protecting cells from immunoglobulins was tested by embedding HLA-typed human lymphocytes, which were subsequently incubated with specific anti-HLA immunoglobulin G and complement. These data show that large yields of porcine hepatocytes that are embedded in coated alginate beads remain functional and are isolated from large molecular weight molecules, such as immunoglobulins. This system represents a promising tool for the design of an extracorporeal bioartificial liver, containing xenogeneic hepatocytes, to treat acute liver disease in humans.

QRS morphology-dependent pharmacodynamics in multiform ventricular ectopic activity.

The effect of an infusion of intravenous procainamide on the frequency of ventricular premature complexes (VCPs) of differing QRS morphologies was studied in 20 patients with multiform ectopic activity. In 17 of 20 patients, there was differential suppression of single VPCs with different QRS morphologies. VPCs of the most frequent QRS morphology and the second most frequent QRS morphology were compared with respect to the procainamide level at the escape of VPCs from 85% suppression and the duration of suppression measured from the onset of the procainamide infusion. In 8 patients, VPCs of the most frequent QRS morphology remained suppressed at lower procainamide concentrations and for longer times than did VPCs of the second most frequent QRS morphology (escape procainamide concentration = 2.8 +/- 1.7 versus 5.4 +/- 2.3 micrograms/ml, p less than 0.025; time to escape 244 +/- 138 versus 98 +/- 114 min; p less than 0.05). In 9 other patients, VPCs of the second most frequent QRS morphology remained suppressed at lower procainamide concentrations and for longer times than did VPCs of the most frequent QRS morphology (escape procainamide concentration 2.9 +/- 1.4 versus 8.3 +/- 6.3 micrograms/ml, p less than 0.025; time to escape 317 +/- 114 versus 63 +/- 80 min; p less than 0.001). Thus, in individual patients there are specific patterns of suppression of VPCs of different QRS morphologies which are independent of the frequency of each morphology. There is apparently a differential pharmacologic effect of procainamide on the foci or pathways responsible for the different QRS morphologies of multiform VPCs.

Pharmacology of the class III antiarrhythmic agent sematilide in patients with arrhythmias.

Sematilide, a close structural analog of N-acetylprocainamide, prolongs cardiac action potentials in vitro, whereas it does not depress maximum action potential upstroke slope, a "class III" action. This report outlines an evaluation of the clinical pharmacologic actions of sematilide in 14 patients with chronic high-frequency nonsustained ventricular arrhythmias. In all, 36 intravenous infusions (range 0.15 to 1.5 mg/kg over 15 minutes) were administered in a dose-ranging, placebo-controlled study design. Sematilide prolonged rate-corrected QT (QTc) in a dose- and concentration-related fashion, did not alter PR or QRS, and slowed heart rate at high concentrations (greater than or equal to 2 micrograms/ml). The relations between dose and total area under the time-concentration curve, dose and peak plasma concentration, and peak plasma concentration and increase in QTc were linear (r = 0.66 to 0.92; p less than 0.001). QTc increases of approximately equal to 25% were seen at plasma concentrations of approximately equal to 2.0 micrograms/ml. The mean elimination half-life (+/- SD) was 3.6 +/- 0.8 hours, and most of a dose (77 +/- 13%) was recovered unchanged in the urine. Plasma concentrations greater than or equal to 0.8 micrograms/ml suppressed arrhythmias (5 patients) or aggravated them (3), including 1 patient who needed cardioversion for an episode of torsades de pointes (2.7 micrograms/ml). Thus, sematilide exerts class III actions in patients. Further studies to evaluate the role of this antiarrhythmic mode of action should be conducted at doses designed to limit QTc increases.

pH-dependent transport of procainamide in cultured renal epithelial monolayers of OK cells: consistent with nonionic diffusion.

1. Previous studies suggest that procainamide is a substrate for organic cation/proton antiport. In order to study the coupling between procainamide flux and proton flux in greater detail we investigated the effects of extracellular procainamide addition upon intracellular pH in cultured monolayers of renal OK cells. Intracellular pH was monitored by use of BCECF as a probe. 2. Apical addition of procainamide (10 mM) caused a significant alkalinisation of intracellular pH. Basolateral addition of procainamide was equally effective in raising intracellular pH. A similar alkalinisation was found in two other renal cell lines: MDCK strain 1 and LLCPK1. 3. In contrast, both tetraethylammonium and N-methylnicotinamide, archetypal substrates for organic cation/proton antiport were without effect upon intracellular pH. 4. At physiological pH values, procainamide exists as a neutral weak base (B) and its conjugate weak acid (BH+). To test which species of procainamide was responsible for the alkalinisation, experiments in which [B] was kept constant whilst [BH+] was varied from 1.15 mM to 7.25 mM were performed. The results suggested that the neutral weak base (B) was the permeant species. 5. Procainamide efflux from procainamide-loaded cell monolayers resulted in a significant acidification of intracellular pH. As with procainamide uptake, this result could be ascribed to the movement of neutral weak base. 6. These effects of procainamide upon intracellular pH are consistent with nonionic diffusion of procainamide rather than an interaction of procainamide with the organic cation/proton antiporter. In addition, the results suggest that organic cation/proton antiport is not highly expressed in OK cells.

Effect of perfused rat mandibular-gland pHI on the ratio of procainamide concentration in saliva to that in venous effluent.

The saliva to venous-effluent concentration ratio (S/E ratio) for procainamide (PA) was determined and compared with the ratio calculated by using the intracellular pH value of glandular cells. Exposed mandibular gland was perfused in situ with Krebs-Ringer bicarbonate buffer containing PA (10-100 micrograms/ml) and acetylcholine (ACh, 0.1 to 10 microM) or pilocarpine (10 microM). These perfusion conditions maintained almost normal physiological function of the mandibular gland throughout the perfusion period of 60 min, since the salivary Na+ and K+ concentrations were kept at almost constant levels, comparable with those reported in vivo, and the salivary flow, pH and protein level were also stabilized. Under fixed stimulation conditions with 1 microM ACh or 10 microM pilocarpine, the perfusate PA concentration ranging from 20 to 100 micrograms/ml did not affect the S/E ratio (approximately 0.3). There was a negative correlation between the S/E ratio and salivary pH when stimulated with 0.1 to 10 microM ACh. However, Matin's equation [S. B. Matin et al., Clin. Pharmac. Ther. 16, 1052 (1974)] employing venous effluent and salivary pH values did not explain fully these observed ratios. In contrast, Borzelleca's model [J. F. Borzelleca and J. W. Putney, J. Pharmac. exp. Ther. 174, 527 (1970)] for salivary drug transport using intracellular pH of the mandibular gland cells predicted S/E ratios relatively close to the observed values when the gland was perfused at pH 7.4 or 8.0.

Procainamide-cimetidine drug interaction in elderly male patients.

Thirty-six hospitalized male patients receiving oral sustained-release procainamide every six hours for the treatment of ventricular arrhythmias were studied at steady-state before and after oral cimetidine 300 mg every six hours for three days. Average age and weight were 73 +/- 12 (SD) years and 76 +/- 10 kg. Patients did not have a myocardial infarction within the last two years or congestive heart failure and had calculated creatinine clearances (CrCl) between 35 and 75 mL/min/70 kg. Ten patients had urine collections that permitted computation of the ratio between the renal clearance of procainamide and CrCl (PA/CrCl) and the renal clearance of n-acetyl-procainamide (NAPA) and CrCl (NAPA/CrCl). The average steady-state procainamide and NAPA concentrations increased 55% and 36%, respectively, during cimetidine treatment (P less than .01). Twelve patients experienced mild to severe symptoms of what may have been procainamide toxicity. Apparent procainamide oral clearance decreased 41% while patients received cimetidine (P less than .01). PA/CrCl and NAPA/CrCl ratios decreased by 33% and 21%, respectively, during cimetidine therapy (P less than .05). Cimetidine therapy given to older male patients taking procainamide can cause steady-state concentrations of procainamide to rise to toxic levels. Patients prescribed this combination should be monitored carefully for adverse side effects.

Effect of probenecid on the pharmacokinetics and pharmacodynamics of procainamide.

Renal tubular transport of organic anions and cations is assumed to be mutually exclusive. However, results of a number of in vitro and in vivo studies suggest an interaction between the organic anion, probenecid, and various organic cations in the proximal renal tubule. To evaluate the clinical importance of such an interaction, the authors investigated the pharmacokinetics and pharmacodynamics of procainamide, an organic cation with a low therapeutic index that is excreted in part by active secretion in the proximal tubule, in the presence and absence of probenecid. In a randomized crossover study, six healthy subjects received a single 750-mg IV dose of procainamide, with and without prior probenecid administration (2 g orally). Blood and urine samples were obtained and pharmacokinetic parameters of procainamide were determined in each treatment period. QT intervals were measured from ECG recordings that were obtained at blood collection times for pharmacodynamic evaluation. Coadministration of probenecid did not result in any significant change in the overall disposition of procainamide. In particular, renal clearance was not significantly different (488 +/- 95 mL/min without probenecid vs. 478 +/- 69 mL/min in the presence of probenecid). Our data suggest an interaction between probenecid and procainamide in the proximal renal tubule does not exit. Reasons for this lack of interaction are discussed.

Pharmacodynamics of procainamide in patients with ventricular tachyarrhythmias.

The onset and offset of the electropharmacologic effect of procainamide was studied in nine patients with ventricular arrhythmias. Procainamide was given at a constant infusion rate of 0.27 +/- 0.05 mg/kg/min for 50 to 60 minutes to an average total dose of 15.5 +/- 4.4 mg/kg. The QRS interval (used as an index of electropharmacologic effect) at a paced cycle length of 500 ms, and the plasma procainamide concentration were measured simultaneously every 5 minutes during infusion and at frequent intervals for up to 4 hours during a washout period. The average peak plasma concentration was 15.8 +/- 9.6 micrograms/ml and the average maximum QRS interval prolongation was 23.9 +/- 6.8% from baseline. The temporal and static plasma concentration-effect relationships were evaluated by pharmacodynamic modeling and linear regression. For six patients, there was a minimal (less than 2 minutes) delay in the plasma concentration-effect relationship, and the data fit a linear relationship with an average slope of 3.2 +/- 1.1 msec/microgram/ml. For the other three patients, there was a significant delay (3, 10, and 18 minutes respectively) in the plasma concentration-effect relationship. In most patients, the electropharmacologic effect of procainamide is rapid and proportional to plasma concentration; but in a minority of patients, significant delay occurs and could influence the results and interpretation of electropharmacologic studies.