Efficacy and tolerance of tocainide during acute and long-term treatment of chronic ventricular arrhythmias

Summary The acute efficacy of tocainide and procainamide was studied in 10 patients with chronic, reproducible ventricular arrhythmia. The drugs were administered in random order, by intravenous infusion, during repeated standardized, submaximal exercise tests. The proposed peak therapeutic plasma concentrations of both drugs were achieved. Both agents had an equal and statistically significant anti-arrhythmic effect; thus, a reduction in ventricular ectopic beat frequency by 70% or more was seen 9 patients after procainamide, and in 7 patients after tocainide. A fall in blood pressure was seen in two patients after procainamide and in one patient after tocainide. No other adverse reaction was observed. The long-term efficacy of tocainide was studied in 19 patients with chronic ventricular arrhythmias. All patients were monitored by 6–8-h electrocardiographic recordings, and 9 of them also during exercise tests. Tocainide 400 mg every 8 h resulted in a mean peak plasma tocainide concentration of 31.6 µmol/l, and caused suppression of ventricular extrasystolic beats by 70% or more in 11 patients. Adverse reactions to tocainide were seen in 14 patients. Gastro-intestinal and central nervous system side effects were most common, which often disappeared after a reduction in dose. In 5 patients adverse effects were more serious (one patient had syncope and 4 patients had skin rashes) and withdrawal of tocainide was required. Eight patients were treated with tocainide for more than 6 months, of whom 7 were restudied after withdrawal of tocainide; arrhythmias reappeared in 5.The studies demonstrate that tocainide is an effective antiarrhythmic drug in selected patients, but the high frequency of adverse effects may limit its long-term use.     

Pharmacokinetics of intravenous and oral tolmesoxide

Summary A high pressure liquid chromatographic assay was developed for simultaneous measurement of the plasma levels of tolmesoxide and its principal metabolite, RX71112. The assay was used to study the disposition of intravenous and oral tolmesoxide in ten normotensive subjects. Two exponential terms were required to describe the disposition of the drug following intravenous administration, whilst a single exponential term sufficied to account for the decay in the plasma concentration after oral administration. The bioavailability of oral tolmesoxide from capsules averaged 84.5% and was independent of dose. The mean half-life after i. v. dosing was 2.6 h (±0.3 SEM) compared to values of 1.9 h (±0.1 SEM) and 2.7 h (±0.5 SEM) following 200 and 400 mg oral doses respectively. In all subjects RX71112 appeared in plasma shortly after tolmesoxide following both routes of administration. The terminal half-life of the metabolite was significantly longer than tolmesoxide with a mean value of 4.9 h (±0.9 SEM) following the 200 mg oral dose of tolmesoxide. The binding of tolmesoxide and RX71112 at therapeutic plasma concentration was 36.8% (±0.5 SEM) and 58.5% (±0.3 SEM) and this remained unchanged at higher concentrations.     

Influence of rifampin on tocainide pharmacokinetics in humans

The effects of metabolic enzyme induction by rifampin on the pharmacokinetics of tocainide were studied in eight healthy volunteers. In an open, unrandomized fashion, volunteers received tocainide hydrochloride 600 mg orally. Blood samples were obtained immediately before and at various time intervals up to 48 hours after the dose. Urine samples were collected before and at various intervals up to 72 hours after the dose. Serum and urine samples were assayed for tocainide content by high-performance liquid chromatography. After a four-week washout period, volunteers ingested 300 mg of rifampin by mouth every 12 hours. After 10 doses, subjects received a second oral dose of tocainide hydrochloride 600 mg, and blood and urine samples were collected as before. During the sampling period, subjects continued to ingest rifampin 300 mg orally every 12 hours. Significant differences in elimination rate constant (average increase, 0.0545 to 0.0748 hr-1), elimination half-life (average reduction, 13.2 to 9.4 hours), oral clearance, and area under the concentration-time curve (average reduction, 76.8 to 55.0 mg.hr/L) between the control and rifampin treatment phases were observed. Volume of distribution and renal clearance of tocainide were not significantly different after rifampin treatment. Tocainide appears to be susceptible to significant drug-drug interactions mediated by metabolic enzyme induction.     

Tocainide. A review of its pharmacological properties and therapeutic efficacy

Tocainide is an antiarrhythmic drug structurally related to lignocaine with similar electrophysiological, haemodynamic and antiarrhythmic effects. In contrast to lignocaine (lidocaine) it is well absorbed after oral administration and has a plasma half-life of about 15 hours. In several open and controlled therapeutic trials in patients with ventricular arrhythmias, often following a myocardial infarction, tocainide has been relatively effective and usually well tolerated. In treating ventricular ectopic beats and/or ventricular tachycardia tocainide has demonstrated effective suppression in 60 to 70% of patients in both open and controlled studies. It has an acute effect when infused in patients with ventricular arrhythmias complicating myocardial infarction, as well as a prophylactic effect when given orally. The majority of these studies have demonstrated tocainide to be more effective than placebo, but trials against other antiarrhythmic agents are few in number and vary in design. One study combining an infusion of tocainide with oral therapy compared to a bolus injection of lignocaine followed by a constant infusion in patients after myocardial infarction, found the two agents to be of similar efficacy. The most common adverse effects are neurological and gastrointestinal in nature, nausea and dizziness occurring most frequently. Adverse effects resulting in termination of therapy have been reported in about 16% of patients. Aggravation of pre-existing heart failure, increased ventricular arrhythmia, deterioration of conduction disturbances, convulsions, and cases of lupus erythematosus syndrome have occasionally been reported. Thus, tocainide appears to offer a worthwhile addition to the other antiarrhythmic agents available for ventricular arrhythmias. However, its relative place in therapy compared with other antiarrhythmic drugs is not yet clearly established.     

Comparative bioavailability of disopyramide after multiple dosing with standard capsules and controlled-release tablets

Summary Plasma concentrations and bioavailability of disopyramide following repeated administration of standard capsules and controlled-release tablets have been compared. Ten patients were randomized into two groups; Group I received disopyramide capsules 150 mg every 6 h for five days and subsequently disopyramide controlled-release tablets 300 mg every 12 h for further five days. Group II received the same preparations in the reverse order. There was a more rapid rise in disopyramide concentration after the capsules: the maximum of 10.7±0.6 µmol/l (mean ± SEM) was reached within 1.8±0.4 h as compared to 10.6±0.4 µmol/l within 4.0±0.3 h after the controlled-release tablets. No significant difference in the fluctuations in individual plasma concentrations during each dose interval at steady state were observed after ordinary capsules compared to controlled-release tablets. The extent of bioavailability was the same. Eight patients reported some side-effects during the capsule period and nine during the controlled-release tablet period.     

Disposition of valproic acid in man

Summary The pharmacokinetics of valproic acid (VPA) have been studied in 6 healthy subjects following a single 600 mg dose, and after multiple doses over 12 days (1200 mg daily) of enteric-coated sodium valproate. A time lag before absorption of 1 to 2 h was observed in each subject, and then absorption was rapid, peak concentrations being recorded 3 to 4 h after administration of the dose. The plasma level decline was biphasic with a terminal half-life of 15.9±2.6 h in the single dose and 17.3±3.0 h in the multiple dose experiments. There was no evidence of dose dependent kinetics or autoinduction. Total plasma clearance was 0.0064±0.0011 l/kg×h. The apparent volume of distribution was small at 0.15±0.2 l/kg. The mean steady state plasma concentration (C_ss) reached after 4 days was 81.3±13.0 µg/ml. C_ss observed was lower than C_ss predicted (99.2±14.7 µg/ml) from single dose kinetics (p<0.001). The difference was probably due to a reduction in plasma protein binding at higher concentrations. VPA concentration in saliva was between 0.4 and 4.5% of the total plasma concentration and was not equal to the concentration of unbound drug in plasma (6.7±0.8% unbound). 3.2% of the dose was excreted in urine as the parent drug and 21.2% as conjugated metabolites.Supported by Sandoz Stiftung für Therapeutische Forschung     

Electrophysiological effects of tocainide on canine subendocardial Purkinje fibers surviving infarction

The effects of 10 and 20 mg/l of tocainide on transmembrane action potential characteristics were examined in Purkinje fibers surviving infarction. Infarcted tissue was obtained from canine hearts 24 h after coronary artery ligation. The preparation was stimulated at basic cycle lengths (BCL) of 1000-300 ms. Tocainide reduced the overshoot and amplitude of Purkinje fibers surviving infarction. The maximum upstroke velocity (Vmax) was decreased by tocainide in a dose dependent manner. This effect was more prominent at the shorter BCL. Statistical analysis revealed a significant interaction of the BCL with the drug effect on overshoot, amplitude, Vmax and action potential durations (APD50% and APD90%). Tocainide reduced the effective refractory period (ERP) at the BCL of 1000 ms, but had no significant effect at the BCL of 300 ms. Membrane responsiveness and steady state characteristics of Vmax were shifted significantly to more negative membrane potentials by tocainide. Investigation of the recovery kinetics of Vmax in the presence of tocainide showed an exponential recovery of Vmax with a time constant of 514 ms. These results support the finding that the effect of tocainide on Vmax and conductions is enhanced at faster rates of stimulation. Thus tocainide may be able to depress conduction to produce bidirectional block in the termination of ventricular tachycardia caused by reentry, while having minimal effect on conduction at normal heart rates.     

Plasma and skin blister fluid concentrations of trimethoprim following its oral administration

Summary Plasma and skin blister fluid concentration-time curves following a single oral dose of trimethoprim have been evaluated. Skin blisters were produced by the cantharides technique, using patches with cantharidin ointment. Trimethoprim concentrations in plasma following multiple doses of 200 mg were also determined. The maximal concentration in plasma after a single oral dose of 400 mg trimethoprim was 3.95±1.08 mg/l, and it was observed after 2 h, whereas in skin blister fluid the level was 2.21±0.62 mg/l, and it was delayed for up to 6 h. This means that a certain time is required for drug transfer from the capillaries via the basal membrane into blister fluid. Penetration of the drug into blister fluid, defined as the ratio of the areas under the trimethoprim level time curve in skin blister fluid to that of plasma, was 0.826±0.096. The steady-state concentration of trimethoprim in plasma during routine treatment with 200-mg doses ranged between 2 and 3.5 mg/l.     

Comparative pharmacokinetic analysis of a novel sustained-release dosage form of theophylline in humans

Summary The pharmacokinetics and relative bioavailability of theophylline from a new sustained-release formulation (Theotard^®) and from a standard sustained-release formulation (Theo-Dur^®) were compared in 6 healthy, adult, male volunteers. After a single oral dose of 300 mg Theotard, a mean maximal plasma concentration (Cb_max of 3.49±1.05 mg/l was obtained after 8 h (t_max). After an identical dose of Theo-Dur, a peak plasma concentration of 4.68±1.33 mg/l was obtained after 6.33 h. The mean relative bioavailability of theophylline from Theotard was 1.02±0.16 relative to that of Theo-Dur. In 5 of the volunteers the Theotard formulation exhibited a more prolonged and uniform absorption rate and yielded more sustained plasma levels.     

Pharmacokinetics and haemodynamic effects of tocainide in patients with acute myocardial infarction complicated by left ventricular failure.

The pharmacokinetics and haemodynamic effects of tocainide, an orally active structural analogue of lignocaine, were studied in patients with acute myocardial infarction complicated by left ventricular failure. Fourteen patients (mean age 65 years) with acute myocardial infarction complicated by mild left ventricular failure were studied, following a single dose of tocainide (250 mg) by intravenous infusion, over 30 min. Heart rate, systemic arterial pressure, pulmonary artery pressure and cardiac output were monitored. Plasma tocainide levels were estimated by gas chromatography. The mean plasma level of tocainide achieved was 2.95 micrograms/ml (15.37 mmol/l). The mean plasma half-life was 15.6 h. The mean cardiac index was reduced 5 min after completion of the infusion, from 2.24 1 min-1 m-2 (+/- 0.40) to 2.07 1 min-1 m-2 (+/- 0.29) (P less than 0.01). At 90 min the cardiac index had returned to pre-treatment levels. Small changes were seen in the heart rate, arterial blood pressure and the pulmonary artery pressure but these changes were not statistically significant. The pharmacokinetics of tocainide were not significantly altered in patients with acute myocardial infarction complicated by mild left ventricular failure.     

Ofloxacin in juvenile non-human primates and rats. Arthropathia and drug plasma concentrations

Arthropathia in juvenile animals is the most important toxic effect induced by quinolones. We conducted pharmacokinetic and morphological studies with ofloxacin on non-human primates (Callithrix jacchus, Marmosets) and rats. In the marmoset, electron microscopy and the application of immuno-morphological methods proved to be suitable for the detection of specific alterations in cartilage (e. g. loss of proteoglycanes and altered chondrocytes). Subsequently performed electron microscopic examinations in rats showed similar specific alterations of the femur cartilage surface after multiple oral applications of 600 mg ofloxacin/kg body wt. These results were correlated with pharmacokinetic data obtained for the same species. After single oral application of 100, 300 or 600 mg ofloxacin/kg body wt to 5 week-old rats peak plasma levels were achieved 15–45 min after administration indicating a rapid absorption of the drug. The following peak concentrations were measured for the three doses applied (mean±SD): 8.9±2.1, 22.6±7.5 mg/l and 33.5±9.8 mg/l, respectively. After 360 min the concentrations were 1.1±0.4, 5.9±2.5 and 15.9±5.1 mg/l, respectively. After subcutaneous injection of 100 mg ofloxacin/kg body wt the mean peak concentration was 27.7±2.6 mg/l after 45 min (0.5±0.2 mg/l after 360 min). In the marmoset higher plasma concentrations were measured with comparable doses. One, 3, and 6 h after the last of nine administrations of 200 mg ofloxacin/kg body wt, the mean (±SD) plasma concentrations were: 42.7±16.7, 40.6±9.5, and 26.5±3.6 mg ofloxacin/l plasma. Typical alterations of the joint cartilage of juvenile rats (e. g. opened chondrocyte cavities, swelling of rough endoplasmic reticulum and mitochondrial swelling in the chondrocytes) were induced by oral administration of ofloxacin at doses that were approximately 100 times higher than therapeutic ones, but led to peak plasma concentrations which were only approximately 10 times above the therapeutic level. Since we found corresponding cartilage alterations in marmosets and rats, this species provides a convenient model for additional studies on chondrotoxic effects of quinolones.     

Pharmacokinetics of meptazinol in man following repeated intramuscular administration

Summary A study was performed in 6 healthy volunteers to determine whether 50 mg intramuscular doses of meptazinol repeated four hourly for 24 h would lead to accumulation of the drug. The first dose of meptazinol was rapidly absorbed with a subsequent mean (± SD) elimination half-life of 1.6±0.33 h. This value was unaffected by the administration of intermediate doses. There was no significant accumulation of the drug; 95% of the steady-state plasma concentration was achieved after a mean (± SD) of 1.9±0.39 and 99% after a mean (± SD) of 2.9±0.63 doses. These findings are consistent with the theoretical prediction for a rapidly absorbed drug with a plasma elimination half-life of 1.6 h. No clinically relevant changes were seen in pulse blood pressure, haematological or biochemical screens. Reported side effects were of a subjective and minor nature.     

Ketoprofen pharmacokinetics and bioavailability based on an improved sensitive and specific assay

Summary A commercial capsule containing 50 mg of ketoprofen (Orudis), a simple capsule containing 50 mg of ketoprofen alone and 50 mg of ketoprofen in an aqueous solution were given as separate doses in a randomized sequence to 12 normal adult males. The areas under the resulting plasma concentration-time curves (AUC) were remarkably consistent for each volunteer. The bioavailability from the commerical capsule relative to that from the solution was 99.7%±10.5% and that from the simple capsule was 102%±10%. After 6 of the volunteers had taken the commercial capsule 6 hourly for thirteen doses, their AUC extrapolated to infinity was significantly higher (by 22%) than that after the single dose indicating, contrary to previous reports, accumulation upon multiple dosing. The interdose AUC after the thirteenth dose was, however, statistically indistinguishable from the AUC-to-infinity after the single dose as might be expected from linear kinetics. The ketoprofen solution generated peak plasma concentrations in only one-third the time (21±7 min) required for the capsules (commercial, 72±45; simple, 61±39 min). Despite plasma concentrations being tracked over a 200-fold range, log linearity was not established within 12 h in any of the 42 profiles obtained. A two-compartment open model was fitted to the solution data giving excellent prediction of the time-to-peak and clearance (Cl/F=5.2±1.1 l/h) as determined by eye and by log-trapezoidal rule, respectively.Deceased, April 4th, 1981     

Placental transfer of pinazepam and its metabolite N-desmethyldiazepam in women at term

Summary Placental transfer of pinazepam and its metabolite N-desmethyldiazepam was investigated in 25 pregnant women at term. Pinazepam was administered orally as a single (10 mg) dose to 13 women, or in multiple doses of 5 mg daily to 12 women. The dose-delivery interval ranged between 1 and 26 h for the single dose, and the period between the last of the multiple doses and delivery was 1.4 to 24 h. Pinazepam and N-desmethyldiazepam were measured in plasma obtained from the umbilical vein and from the mother, at delivery. Pinazepam was only detectable in plasma after the 10 mg dose. The drug did not reach an apparent equilibrium between fetal and maternal plasma. The average (±SEM) cord/maternal ratio of plasma pinazepam concentrations was 0.64±0.07. N-desmethyldiazepam was detectable on each occasion. Its concentration in the plasma from the cord vein became higher than that in the maternal specimens 1–2 h after administration of the parent drug. Little N-desmethyldiazepam was excreted in breast milk.     

Absorption of enprofylline from the gastrointestinal tract in healthy subjects

Summary Enprofylline, a new potent bronchodilator xanthine drug, was given orally as an aqueous solution to 6 healthy subjects in single doses of 2, 4 and 6 mg/kg. The two lower doses produced plasma concentrations in the range 1–4 mg/l, i.e. in the assumed therapeutic interval according to previous animal studies. A high 24 h urine recovery of unchanged drug, with mean values for the three dose levels ranging from 85 to 91% of the given dose, indicated good absorption and little metabolism. The dose-corrected area under the plasma concentration-time curve rose with dose as the latter was increased from 2 to 6 mg/kg. This indicates that the elimination of enprofylline is capacity-limited at high doses. Double peaks in the plasma concentration-time curves at the higher dose levels suggested intermittent and delayed gastric emptying as a possible explanation. This hypothesis was confirmed by studies in 6 other healthy subjects, who received the drug solution by three different routes; by mouth, via a catheter in the duodenum, and rectally via a catheter in the colon. The corresponding time to peak values (mean±SEM) were 32.5±8.7, 13.3±2.5, and 157±23 min.     

Pharmacokinetic studies with chlorthalidone (hygroton®) in man

Summary The kinetics of chlorthalidone in blood and urine were analysed in one group of 6 healthy volunteers after single oral doses of 50, 100 and 200 mg, as well as in a second group of 6 volunteers during and after daily oral doses of 50 mg for 14 days. The mean maximal concentrations recorded in blood 8 h after the three different doses were 3.15 µg/ml (SD±0.52), 5.55±1.58 µg/ml and 7.93±1.40 µg/ml, respectively. Disappearance of chlorthalidone from blood followed an apparent first order type of reaction, the average half life t₅₀ being 49 h (SD 11 h). Total renal elimination of unchanged chlorthalidone amounted to 53.3±8.7%, 46.1±8.4% and 34.0±7.3% of the single 50, 100 and 200 mg doses. Between the 6th and 14th days of daily treatment the concentration at the end of the 24 h dose interval was 7.2±1.4 µg/ml (± 1.4) in blood and 186±44 ng/ml in plasma. Except in the early absorption phase after each dose, the distribution of chlorthalidone between erythrocytes and plasma was constant, the average plasma concentration being 1.38±0.28% (n=75) of the whole blood concentration. At steady state during daily dosing with chlorthalidone 50 mg, the renal elimination of unchanged chlorthalidone within each 24 h dose interval was 57±11.2% of the daily dose. The renal plasma clearance ranged from 46 to 70 ml/min. Following termination of repeated administration the concentration of chlorthalidone in blood decreased with a t₅₀=50±5 h and in plasma with t₅₀=49±4.8 h.     

Serum and saliva levels of a trimethoprim-sulfamethopyrazine combination in man

Summary The pharmacokinetics, hypotensive effect and tolerability of a new vasodilator, tolmesoxide (T), have been studied in 6 uncontrolled hypertensive patients receiving atenolol and a diuretic. After a 50 mg oral dose mean (± SD) peak plasma concentration of T was 1.13±0.29 µg/ml^–1 and occurred 0.79±0.40 h after the dose; mean peak plasma concentration of its sulphone metabolite (M) was 0.37±0.09 µg/ml^–1 at 1.92±1.32 h after the dose. Following peak plasma concentrations there was a monoexponential decline in T and M concentrations with half-lives of 2.78±0.77 h and 10.78±7.85 h respectively. There was a linear increase in plasma concentration of T and M during incremental dosing with 50–200 mg t. i. d. During in-patient administration of 600–900 mg T daily (n=6) there was no significant change in blood pressure, pulse rate or body weight. Out-patient administration of 900 mg T daily (n=4) was associated with a significant fall in mean systolic but not diastolic bp (lying –15/+1 mm Hg. standing –25/–8 mm Hg). A further fall was observed in 2 subjects receiving 1200 mg and 1500 mg daily. Supine pulse rate increased (mean ± SD) significantly from 55±5/min to 66±8/min following 900–1500 mg T in 4 out-patients. Severe nausea and other gastro-intestinal side-effects in all subjects receiving 600–900 mg daily eventually necessitated drug withdrawal. In its present from T is not recommended for the treatment of hypertension.     

Pharmacokinetics of haloperidol in psychotic patients

Nine psychotic patients under continuous oral treatment with haloperidol were randomly given a test dose of 1.5–5 mg haloperidol orally and/or intravenously. Serum levels of haloperidol were determined by high performance liquid chromatography and serum concentration data obtained were submitted to pharmacokinetic analysis. The steady state concentration ratio between blood and plasma was determined and found to be 0.79±0.03. The blood clearance was then calculated to be 550±133 ml/min. The mean hepatic extraction ratio was intermediate (0.37). Consequently, for a drug mainly eliminated by hepatic metabolism like haloperidol, the total blood clearance and the extent of oral bioavailability can be affected by changes in hepatic blood flow, hepatic enzyme activities and drug binding. During continuous oral treatment with haloperidol, however, it can be shown that changes in the total metabolic capacity of the liver due to hepatic enzyme induction or inhibition should be important for the therapeutic effects of haloperidol. The volume of distribution at steady state (Vdss) was large (7.9±2.5 l/kg). The terminal half-life was 18.8 h after intravenous and 18.1 h after oral administration. The oral bioavailability (0.60±0.18) were in accordance with previous results in healthy subjects. A mean lag time after oral dose was 1.3±1.1 h and a longer absorption half-life (1.9±1.4 h) was found in the patients compared with healthy volunteers.     

The pharmacokinetics of atovaquone and proguanil in pregnant women with acute falciparum malaria

Objective To determine the pharmacokinetic properties of atovaquone, proguanil, and the triazine metabolite cycloguanil in women with recrudescent multi-drug resistant falciparum malaria during the second and third trimesters of pregnancy treated by artesunate-atovaquone-proguanil.Methods Serial plasma concentrations of atovaquone, proguanil and cycloguanil were measured in 24 women at baseline and after the final dose of the 3-day treatment with atovaquone (20 mg/kg/day) plus proguanil (8 mg/kg/day) plus artesunate (4 mg/kg/day) daily.Results The triple combination was well tolerated and highly effective. The outcomes of pregnancy were all normal. Population mean (± SEM) oral clearance (Cl/F) estimates were 313±33 ml/h/kg and 1109±43 ml/h/kg, total apparent volume of distribution (Vd/F) 13.0±1.3 l/kg and 22.9±1.4 l/kg, and terminal elimination half-life; 29.1 h and 14.3 h, for atovaquone and proguanil, respectively. Using conventional and population pharmacokinetic analyses, Cl/F and Vd/F estimates for both drugs were approximately twice, and plasma concentrations less than half those reported previously in healthy subjects and patients with acute malaria.Conclusion Artesunate-atovaquone-proguanil is a promising treatment for multi-drug resistant falciparum malaria during pregnancy, but the dose of atovaquone-proguanil may need to be increased.     

The effect of tocainide on theophylline metabolism.

The effect of 5 days of oral tocainide (400 mg every 8 h) on the kinetics of theophylline given as a single 5 mg kg-1 i.v. infusion over 30 min was investigated in eight healthy male nonsmokers. Treatment with tocainide decreased the plasma clearance of theophylline from 37.5 +/- 6.9 (mean +/- s.d.) to 33.7 +/- 5.0 ml kg-1 h-1 (difference -3.8, 95% CI, -1.7 to -5.9; P = 0.004) and increased its terminal elimination half-life from 9.7 +/- 2.5 to 10.4 +/- 2.1 h (difference 0.7, 95% CI, 0.2 to 1.2; P = 0.011). Tocainide decreased the formation clearances of 3-methylxanthine and 1-methyluric acid, but the formation clearance of 1,3-dimethyluric acid was unaltered. These data indicate that tocainide exerts a modest inhibitory effect on theophylline metabolism. The magnitude of this change is substantially smaller than that reported to be produced by mexiletine.