Development, validation and long-term evaluation of a liquid chromatography-tandem mass spectrometry method for simultaneous quantification of amiodarone, desethylamiodarone and mexiletine in human plasma and serum.

Amiodarone and mexiletine are used for ventricular arrhythmias, for which a combination therapy of both anti-arrhythmic drugs (AADs) is not uncommon. Therapeutic drug monitoring (TDM) can be beneficial for clinical guidance of therapy, especially to correctly identify adverse events. Desethylamiodarone, the active metabolite of amiodarone, accumulates over time and is associated with serious adverse events. Therefore, simultaneous TDM for amiodarone, desethylamiodarone and mexiletine is advantageous in clinical practice. The presented LC-MS/MS method was validated for selectivity, matrix effect, linearity, accuracy, precision, carry-over and stability. The method was continuously evaluated during eight months of clinical use. The method was shown to be linear within the measured range of 0.1 to 10 mg/L for each component. The matrix effect was considered negligible. No interfering responses were found for amiodarone, desethylamiodarone and the isotopic-labeled internal standards. A constant and reproducible within-run contribution of 45.3 %, originating from the system, was identified for mexiletine. The systemic contribution to the peak area of the lowest quantifiable concentration of mexiletine affected the selectivity and carry-over effect measurements. Multiple measurements showed that regression adjusted concentrations were accurate and reproducible, indicating calibration correction was applicable. Sample stability was found to be within limits for all storage conditions and freeze-thaw cycles. Furthermore, long-term method evaluation with external controls resulted in stable measurements with a percentage coefficient of variance between 1.3 % and 6.3 %. The presented practical and reliable method is applicable for clinical TDM and will allow clinical practitioners to guide drug therapy of amiodarone and mexiletine.

Surfactant-assisted dispersive liquid-liquid microextraction combined with field-amplified sample stacking in capillary electrophoresis for the determination of mexiletine and lidocaine.

A sensitive method for the determination of mexiletine and lidocaine using surfactant-assisted dispersive liquid-liquid microextraction coupled with capillary electrophoresis was developed. Triton X-100 and dichloromethane were used as the dispersive agent and extraction solvent, respectively. After the extraction, mexiletine and lidocaine were analyzed using capillary electrophoresis with ultraviolet detection. The detection sensitivity was further enhanced through the use of field-amplified sample stacking. Under optimal extraction and stacking conditions, the calibration curves were linear over a concentration range of 0.05-1.00 µM for mexiletine and 0.03-1.00 µM for lidocaine. The limits of detection (signal-to-noise ratio of 3) were 0.01 and 0.01 µM for mexiletine and lidocaine, respectively. An approximately 1141- to 1250-fold improvement in sensitivity was observed for the two analytes compared with the injection of a standard solution without the surfactant-assisted dispersive liquid-liquid microextraction and field-amplified sample stacking procedures. This developed method was successfully applied to the determination of mexiletine and lidocaine in human urine and serum samples. Both precision and accuracy for urine and serum samples were less than 8.7 and 6.7%, respectively. The recoveries of the two analytes from urine and serum samples were 54.7-64.9% and 16.1-56.5%, respectively.

Antiarrhythmic Mexiletine: A Review on Synthetic Routes to Racemic and Homochiral Mexiletine and its Enantioseparation.

Mexiletine is an oral class IB antiarrhythmic agent. Although it was primarily studied for the treatment of ventricular arrhythmias, it has been demonstrated to be useful also for the treatment of chronic painful diabetic neuropathy, neuropathic pain, skeletal muscle channelopathies, and recently amyotrophic lateral sclerosis. This review presents a detailed report on the different synthetic routes to racemic and homochiral mexiletine developed in the last decades, as well as analytical studies regarding enantioseparation methods and enantiomeric excess determination. Finally, some analogues of mexiletine reported in the literature, most of which along with pharmacological studies, have been mentioned.

Quantitation of Flecainide, Mexiletine, Propafenone, and Amiodarone in Serum or Plasma Using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS).

Flecainide, mexiletine, propafenone, and amiodarone are antiarrhythmic drugs that are used primarily in the treatment of cardiac arrhythmias. The monitoring of the use of these drugs has applications in therapeutic drug monitoring and overdose situations. LC-MS/MS is used to analyze plasma/serum extracts with loxapine as the internal standard to ensure accurate quantitation and control for any potential matrix effects. Positive ion electrospray is used to introduce the analytes into the mass spectrometer. Selected reaction monitoring of two product ions for each analyte allows for the calculation of ion ratios which ensures correct identification of each analyte, while a matrix matched calibration curve is used for quantitation.

Translation of flecainide- and mexiletine-induced cardiac sodium channel inhibition and ventricular conduction slowing from nonclinical models to clinical.

INTRODUCTION: Nonclinical in vivo models used for cardiovascular safety testing have not previously been studied for their sensitivity for detection of conduction slowing resulting from cardiac sodium channel block. The goal of this study was to examine the sensitivity of in vivo models to cardiac sodium channel block, and translation of the effect from in vitro to in vivo models using sodium channel inhibitors flecainide and mexiletine; flecainide, but not mexiletine is commonly associated with QRS complex prolongation in humans. METHODS: Inhibition of cloned cardiac sodium channels (hNav1.5) was studied using the IonWorks platform. Conduction slowing was measured in vitro in the rabbit isolated ventricular wedge (RVW) and in vivo in the conscious telemetered rat and dog, and anaesthetised dog. RESULTS: Flecainide and mexiletine inhibited hNav1.5 channels with IC50 values of 10.7 and 67.2 µM respectively. In the RVW, QRS was increased by flecainide at 60 bpm, and at 120bpm, there was an increased effect of both drugs. In conscious rats, flecainide significantly increased QRS complex duration; mexiletine had no significant effect, but there was an increase at the highest dose in 4/6 animals. QRS complex was increased by flecainide and mexiletine in anaesthetised dogs but this was not statistically significant; in conscious dog, only flecainide produced a significant increase in QRS complex. DISCUSSION: When compared to clinical data, effects of flecainide and mexiletine in RVW and conscious dog compared well with effects in patients and healthy volunteers in terms of sensitivity. The anaesthetised dog was least sensitive for detection of changes in QRS. All assays showed some differentiation between the expected conduction slowing activity of flecainide and mexiletine. Based on these data, RVW and conscious dog were most predictive for effects of compounds on QRS complex and cardiac conduction.

Column-switching HPLC determination of mexiletine using tris(bipyridine)ruthenium(III) electrogenerated chemiluminescence and precolumn derivatization with divinylsulfone.

A sensitive HPLC method combined with a column-switching system and tris(bipyridine)ruthenium(III) electrogenerated chemiluminescence (ECL) detection has been developed for the quantitative determination of mexiletine (MEX). MEX was derivatized by divinylsulfone (DVS) and then measured. The optimum conditions for the derivatization reaction were 10 µL of sample solutions, 40 mM DVS (pH 8.0), a reaction temperature of 50°C, and a reaction time of 15 min. The derivatized samples were cleaned up by an on-line pretreatment column. Also, after column-switching to the analytical column, the derivatized MEX was separated and detected. The calibration curves of MEX in human control serum showed good linear regression (r = 0.9996) from 0.008 to 6.56 µg ml(-1). The detection limit of MEX was 0.008 µg ml(-1) (S/N = 3). At a concentration of 2.0 µg ml(-1) MEX, the relative standard deviation (n = 5) was 0.98%. In this method the concentration of MEX in human control serum was readily measured, and this method was successfully applied to the time courses of the concentration of MEX in rabbit plasma after intravenous administration. The proposed method involved a simple and minimum sample-preparation procedure and a short run time (<20 min). Therefore it can be applied to routine therapeutic monitoring and pharmacokinetic studies of MEX.

Combination therapy with mexiletine and sotalol suppresses inherited ventricular arrhythmias in German shepherd dogs better than mexiletine or sotalol monotherapy: a randomized cross-over study.

OBJECTIVES: To determine the spontaneous variability of ventricular arrhythmias (VA) and evaluate anti-arrhythmic efficacy of mexiletine, sotalol, and a mexiletine-sotalol combination in German shepherd dogs (GSD) with inherited arrhythmias. ANIMALS, MATERIALS AND METHODS: 12 affected GSD, median age 20 weeks, received mexiletine (8 mg/kg PO q8 h), sotalol (2.5 mg/kg PO q12 h), and combination therapy for 6 days in random order. Pre- and post-treatment 24 h Holter recordings were acquired, allowing determination of VA variability and reduction in 24 h VA for each treatment. Drug concentrations during each arm were measured. RESULTS: An anti-arrhythmic effect could be inferred if ventricular premature complexes (VPC), ventricular couplets (V(cpl)), ventricular tachycardia runs (VT(runs)) and total ventricular ectopy (VE(tot)) frequency were reduced by 61%, 97%, 98%, and 63% (1 control Holter model), by 53%, 94%, 95%, and 54% (4 control Holter model) and by 54%, 95%, 96% and 56% (3 control Holter model). Combination therapy reduced VPC and VE(tot) in more dogs (5/12 and 6/12) than mexiletine (1/11 and 2/11) or sotalol (2/9 and 1/9) (p < 0.05). The combination therapy reduced the mean number of VPC, V(cpl), and VE(tot). Sotalol monotherapy produced an increase in VT(runs). Plasma mexiletine concentration was higher during combination therapy than with monotherapy. CONCLUSIONS: Combination therapy reduced VPC in affected GSD. Sotalol monotherapy increased VT(runs). Combination therapy increased plasma mexiletine concentrations.

Fabrication and evaluation of chiral monolithic column modified by beta-cyclodextrin derivatives.

Based on combination of chiral recognition ability of beta-cyclodextrin (beta-CD) derivatives and flexibility of monolithic material, a series of chiral stationary phases (CSPs) were prepared by the immobilization of beta-CD and three of its derivatives to the epoxy-activated poly(glycidyl methacrylate-co-ethylene dimethacrylate) monolith under mild condition. Immobilization condition for the connection reaction by different functional groups and bonding ways was studied to obtain good enantiomer selectivity. Prepared CSPs were evaluated by separating racemic mixtures of eight amino acids and two chiral drugs with capillary electrochromatography (CEC).

Pharmacokinetic study of three cardiovascular drugs by high-performance liquid chromatography using pre-column derivatization with 9,10-anthraquinone-2-sulfonyl chloride.

A new method was developed to analyze three cardiovascular drugs in rat plasma, Mexiletine hydrochloride (MXL), Methoxamine hydrochloride (MTX), and Metaraminol bitartrate (MTR), by high-performance liquid chromatography (HPLC) using 9,10-anthraquinone-2-sulfonyl chloride (ASC) as the derivatization reagent. The derivatization modes and conditions for this method were optimized. The quantitative analysis was achieved using a C18 column at room temperature (25 degrees C), with various volume ratios of methanol-water as the mobile phase and a detection wavelength at 256 nm. Analytical linearity was obtained for the method over the concentration range of 0.04-8.0 microg mL(-1) for all the three drugs. The lower limit of quantification (LLOQ) was 0.04 microg mL(-1). This method was successfully applied to the analysis of the three drugs in rat plasma and their pharmacokinetic studies. The t1/2 values of the three drugs in rats were found to be 5.38+/-0.61, 4.49+/-0.53, and 3.70+/-0.19 h for MXL, MTX, and MTR, respectively.

[Determination of mexiletine in human blood by liquid chromatography-tandem mass spectrometry].

OBJECTIVE: To establish a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for detection of mexiletine by liquid chromatography tandem mass spectrometry. METHODS: After simple protein precipitation of the blood sample with acetonitrile, the organic solvent layer diluted with LC mobile solvent was separated by Allure PFP Propyl column, confirmed and quantified by MS/MS in the multi-reaction monitoring (MRM) mode via positive electrospray ionization. RESULTS: Mexiletine and naloxone (internal standard) got ideal resolution under the selected analytical condition. The correlation coeficient of linear calibration curve was over 0.9999 within the mexiletine concentration range 0.02-10 microg/mL. The relative standard deviations were under 10% for intra-day and under 15% for inter-day, and the detection limit was 0.01 microg/mL. CONCLUSION: The established LC-MS/MS method is simple, rapid, sensitive, unaffected by matrix effect and appropriate for detection of mexiletine in blood in the field of therapeutic drug monitoring and forensic toxicology.

Simultaneous determination of ten antiarrhythic drugs and a metabolite in human plasma by liquid chromatography--tandem mass spectrometry.

A simple, accurate and selective LC-MS/MS method was developed and validated for simultaneous quantification of ten antiarrhythic drugs (diltiazem, amiodarone, mexiletine, propranolol, sotalol, verapamil, bisoprolol, metoprolol, atenolol, carvedilol) and a metabolite (norverapamil) in human plasma. Plasma samples were simply pretreated with acetonitrile for deproteinization. Chromatographic separation was performed on a Capcell C(18) column (50mmx2.0mm, 5microm) using a gradient mixture of acetonitrile and water (both containing 0.02% formic acid) as a mobile phase at flow rate of 0.3ml/min. The analytes were protonated in the positive electrospray ionization (ESI) interface and detected in multiple reaction monitoring (MRM) mode. Calibration curves were linear over wide ranges from sub- to over-therapeutic concentration in plasma for all analytes. Intra- and inter-batch precision of analysis was <12.0%, accuracy ranged from 90% to 110%, average recovery from 85.0% to 99.7%. The validated method was successfully applied to therapeutic drug monitoring (TDM) of antiarrhythic drugs in routine clinical practice.

The effect of intravenously administered mexiletine on tinnitus - a pilot study.

The effect of intravenously administered mexiletine on subjective tinnitus and hearing was studied in six patients, who initially responded positively to lidocaine. Distinct mexiletine-induced decreases in tinnitus loudness were demonstrated in three subjects, as reflected by maximum VAS (visual analogue scale) level reduction of 34%, 95%, and 100%, respectively. One subject reported change in tinnitus pitch, another one showed a slight (18% on VAS) tinnitus reduction, and one subject disclosed no effect. Side effects were seen only during one of seven infusions. Mexiletine induced shifts in pure-tone threshold, transient evoked otoacoustic emission, and acoustic reflex threshold, probably reflecting a reversible interference in the function of organ of Corti. The concentration effect relationship remained unclear and no general 'therapeutic' level could be identified. This study confirms the effect of mexiletine on the auditory function and its potential as a possible therapeutic agent or a model for further development in tinnitus pharmacotherapy.

Effect of congestive heart failure on mexiletine pharmacokinetics in a Japanese population.

OBJECTIVE: The goal of this study was to evaluate the influence of congestive heart failure (CHF) on the clearance of mexiletine. METHODS: The mexiletine clearance/bioavailability (CL/F) ratio was estimated in 584 inpatients receiving mexiletine therapy. The study population consisted of 210 patients with CHF [CHF group; 116 inpatients with New York Heart Association (NYHA) class I-II (group NYHA I-II) CHF and 94 inpatients with NYHA class III-IV (group NYHA III-IV) CHF] and 374 inpatients without CHF (Non-CHF group). Serum levels of mexiletine were determined by high performance liquid chromatography (HPLC). RESULTS: Mexiletine clearance was significantly lower in the CHF group when compared with the Non-CHF group (0.264+/-0.093 vs. 0.393+/-0.082 l/h/kg, mean+/-S.D., p<0.05). Further, the CL/F ratio was 50% lower in group NYHA III-IV when compared with the Non-CHF group, and the CL/F ratio tended to change in inverse proportion to NYHA class. CONCLUSION: CHF status significantly affects mexiletine clearance. Therefore, dose adjustments and careful monitoring are likely required in CHF patients receiving mexiletine.

New potent mexiletine and tocainide analogues evaluated in vivo and in vitro as antimyotonic agents on the myotonic ADR mouse.

The antimyotonic activity of chiral derivatives of mexiletine and tocainide, selected as potent use-dependent blockers of skeletal muscle sodium channels, was evaluated in vivo acutely in myotonic ADR mice. The compounds had either aromatic (Me4 and Me6) or branched isopropyl groups (Me5 and To1) on the asymmetric centre, or had this latter one methylene apart from the amino group (Me2). Therapeutic doses of mexiletine (5-10 mg/kg) and tocainide (7-20 mg/kg) significantly reduced the long time of righting reflex (TRR), typical of ADR mice. Me4, Me5 and Me6 were 2-fold more potent than mexiletine. To1 fully normalised the TRR at 7 mg/kg. The electromyographic analysis confirmed a muscle-based activity for drug effectiveness on TRR. All the compounds reduced the myotonic hyperexcitability of intercostal muscle fibres when tested in vitro by current-clamp recordings, with a potency correlated with their action on sodium channels. On stimulus-evoked firing, the isopropyl analogues were 2-4-fold more potent than parent compounds, while the aromatic analogues were about 10-fold more potent than mexiletine. Patch-clamp recordings confirmed a normal-like pharmacological sensitivity of sodium channels of native ADR muscle fibres. Finally, the in vivo antimyotonic activity is due to the block of sodium channels and divergences with in vitro potency can be related to structure-based changes in drug pharmacokinetics.

[HPLC-fluorescent spectrometric determination of serum mexiletine concentration after derivatization with fluram].

AIM: To establish an HPLC-fluorescent spectrometric method for the determination of mexiletine hydrochloride in plasma after derivatization with fluram. METHODS: Fluram acetone solution was added to the deproteinized plasma with acetone to obtain the derivative of mexiletine. The HPLC method was performed on a column of Allitima C18 (150 mm x 4.6 mm, 5 microns) with the mobile phase of methanol-water-diethylamine-phosphoric acid buffer (2.4 mol.L-1, pH 4.0) (70:28:2), and the detective wavelength were set at Ex 392 nm and Em 480 nm. RESULTS: Mexiletine has a liner range over the concentration range from 0.100-6.400 mg.L-1. The lowest detectable concentration of this method was 5 micrograms.L-1 (S/N > or = 4). The intra-day and inter-day RSDs were 1.34%-5.31%, respectively. CONCLUSION: This method is simple, selective and can be used for therapeutic drug monitoring (TDM) and pharmacokinetic studies of mexiletine.

Development of enzyme-linked immunosorbent assay for therapeutic drug monitoring of mexiletine.

This paper reports a sensitive and specific enzyme-linked immunosorbent assay for determination of the antiarrhythmic drug mexiletine in human serum. Anti-mexiletine antibody was obtained by immunizing rabbits with an antigen conjugated with mercaptosuccinyl bovine serum albumin using N-(epsilon-maleimidocaproyloxy)succinimide as a heterobifunctional coupling agent. Enzyme labeling of mexiletine with beta-D-galactosidase was performed using glutaraldehyde. In this assay, the mexiletine to be quantified is chemically modified by acetic anhydride allowed to compete with a mexiletine-beta-D-galactosidase conjugate for binding to a limited amount of an anti-mexiletine antibody which was used to coat the wells of a microtiter plate. Mexiletine concentrations lower than 80 ng/ml were measurable reproducibly by the enzyme-linked immunosorbent assay. This assay was specific for mexiletine and showed very slight cross-reactivity with its major metabolite, 2-hydroxymethylmexiletine (1.5%), but none with p-hydroxymexiletine. The values of serum mexiletine levels from 15 patients by this enzyme-linked immunosorbent assay were comparable with those measured by HPLC. There was a good correlation between the values determined by the two methods. The enzyme-linked immunosorbent assay should be a valuable tool in therapeutic drug monitoring and pharmacokinetic studies of mexiletine.

Effects of disopyramide and mexiletine on the terminal repolarization process of the in situ heart assessed using the halothane-anesthetized in vivo canine model.

This study was designed to assess the effects of typical class I drugs on the terminal repolarization process of the in situ heart, which is a useful marker of the potential of drug-induced long QT syndrome. Disopyramide (0.3 and 3.0 mg/kg per 10 min, n = 6) or mexiletine (0.3 and 3.0 mg/kg per 30s, n = 6) was intravenously administered to halothane-anesthetized beagle dogs under the monitoring of multiple cardiovascular parameters. Antiarrhythmic concentrations were obtained with the high dose of each drug. The low dose of disopyramide or mexiletine hardly affected any of the electrophysiological parameters assessed. The high dose of disopyramide prolonged the monophasic action potential duration (MAP90) and effective refractory period (ERP) to a similar extent, thus displacing the terminal repolarization period backward, which might provide a potential proarrhythmic substrate, particularly at a slow heart rate. On the other hand, the high dose of mexiletine shortened the MAP90, but prolonged the ERP, resulting in the disappearance of the terminal repolarization period, which could prevent premature excitation with its associated conduction slowing. These electrophysiological effects of disopyramide and mexiletine on the terminal repolarization phase may at least in part explain their clinically described antiarrhythmic and proarrhythmic properties.

Possible mechanism for pharmacokinetic interaction between lidocaine and mexiletine.

OBJECTIVE: Our objective was to elucidate the mechanism of pharmacokinetic interaction between lidocaine and mexiletine, because an unexpected increase in plasma lidocaine concentration accompanied by severe side effects was observed when mexiletine was administered to a patient with dilated cardiomyopathy. METHODS: Plasma concentrations of lidocaine, its major metabolites, and mexiletine were measured in a patient with dilated cardiomyopathy. The lidocaine-mexiletine interaction was evaluated by examination of the effects of mexiletine on plasma concentration and the tissue distribution of lidocaine in rabbits in vivo, as well as on the in vitro lidocaine binding to phosphatidylserine, a binding constituent for weakly basic drugs. RESULTS: Plasma lidocaine concentrations increased significantly when the oral dose of mexiletine was increased. This pharmacokinetic interaction was not attributable to a metabolic interaction as evaluated by plasma lidocaine metabolites concentrations. In rabbits, mexiletine seemed to decrease the total plasma clearance of lidocaine, resulting in increased plasma lidocaine concentrations. Mexiletine significantly reduced the tissue distribution of lidocaine to the kidneys and lungs. A strong displacing effect of mexiletine on the binding of lidocaine to phosphatidylserine was observed in vitro. CONCLUSIONS: A drug interaction derived from the displacement of lidocaine from tissue binding sites by mexiletine that resulted in the increased plasma lidocaine concentrations was shown. This observation had implications for loading doses and acute effects of lidocaine in the concurrent therapy of lidocaine and mexiletine.

Lack of interaction between amiodarone and mexiletine in cardiac arrhythmia patients.

Amiodarone has pharmacokinetic interactions with various therapeutic agents, including phenytoin, flecainide, and cyclosporine. Mexiletine is metabolized by CYP2D6 and CYP1A2. The objective of this study is to evaluate the effect of amiodarone on the pharmacokinetics of mexiletine through its inhibition of various cytochrome P450 (CYP) subtypes. In a series of 181 inpatients with supraventricular tachyarrhythmias, 26 inpatients received mexiletine and amiodarone therapy (MEX + AMD group), and the others received mexiletine therapy (MEX group). In 10 inpatients of the MEX + AMD group, the mexiletine clearance (CL(MEX)/F) before and after coadministration of amiodarone was compared. CL(MEX)/F was also compared in the MEX and MEX + AMD groups after the start of amiodarone therapy. Serum mexiletine, amiodarone, and desethylamiodarone concentrations were measured by an HPLC method. The CL(MEX)/F was estimated by the Bayesian method using population pharmacokinetic analysis. There was no significant difference in CL(MEX)/F before and after 1-month coadministration of amiodarone in 10 inpatients of the MEX + AMD group. Although serum amiodarone and desethylamiodarone concentrations gradually increased with time after the start of amiodarone therapy in these patients, CL(MEX)/F showed no change at 3 and 5 months after the start of amiodarone therapy. There was no significant difference in CL(MEX)/F of the MEX group and the MEX + AMD group. The results suggest that the pharmacokinetics of mexiletine is not affected by amiodarone in patients with cardiac arrhythmias.

Effect of fluvoxamine on the pharmacokinetics of mexiletine in healthy Japanese men.

BACKGROUND AND OBJECTIVES: Fluvoxamine, a selective serotonin reuptake inhibitor, is known to inhibit several hepatic cytochrome P450 (CYP) isozymes, in particular CYP1A2. Mexiletine is mainly catalyzed by CYP2D6 and partially catalyzed by CYP1A2. Our objective was to study the potential pharmacokinetic interaction between fluvoxamine and mexiletine. METHODS: A randomized crossover design with two phases was used. A 7-day washout period separated the two treatment conditions. In the one phase, 6 healthy Japanese men received an oral dose of 200 mg of mexiletine alone (study 1); in the other phase, the men received fluvoxamine (50 mg twice a day) for 7 days, and on the eighth day they received oral mexiletine (200 mg) and fluvoxamine concomitantly (study 2). The concentrations of mexiletine were measured with HPLC. RESULTS: The area under the concentration-time curve and serum peak concentration of mexiletine in study 2 were significantly increased compared with those in study 1 (10.4 +/- 4.85 versus 6.70 +/- 3.21 microg x h/mL, P =.006 and 0.623 +/- 0.133 versus 0.536 +/- 0.164 microg/mL, P =.008, respectively). CONCLUSION: The effect of fluvoxamine on the mexiletine disposition is comparatively large, and when mexiletine and fluvoxamine are coadministered careful monitoring of mexiletine is needed.