Pharmacokinetic and pharmacodynamic interaction between mexiletine and propafenone in human beings*1

44

Antiarrhythmic treatment with a single agent isoften ineffective and can be limited by concentration-dependent side effects. Therefore a combination ofantiarrhythmic drugs in smaller and well-tolerateddoses is advocated in cases that do not respond totreatment with single agents. Although beneficialelectropharmacologic interactions are anticipated,combined administration of antiarrhythmic drugs alsocarries the risk of pharmacokinetic drug interactions.

Mexiletine, a class Ib antiarrhythmic agent, possessesdesirable electrophysiological and hemodynamic prop-erties for its combination with other antiarrhythmicagents.1 This has become a significant asset for the clin-ical use of mexiletine because combination therapy isoften required with the drug as a result of a disappoint-ing efficacy when mexiletine is used alone.2 The com-bination of mexiletine with antiarrhythmic drugs, such

Pharmacokinetic and pharmacodynamicinteraction between mexiletine andpropafenone in human beings

Background and objective: Mexiletine and propafenone are often used concomitantly and are metabolizedby the same cytochrome P450 isozymes, namely CYP2D6, CYP1A2, and probably CYP3A4. Our objec-tive was to study the potential pharmacokinetic and electrophysiological interactions between mexiletineand propafenone.Methods: Fifteen healthy volunteers, 8 extensive metabolizers and 7 poor metabolizers of CYP2D6, receivedoral doses of mexiletine 100 mg two times daily from day 1 to day 8 and oral doses of propafenone 150mg two times daily from day 5 to day 12. Interdose studies were performed at steady-state on mexiletinealone (day 4), mexiletine plus propafenone (day 8), and propafenone alone (day 12).Results: In subjects in the extensive metabolizer group, coadministration of propafenone decreased oral clear-ances of R-(–)-mexiletine (from 41 ± 11 L/h to 28 ± 7 L/h) and S-(+)-mexiletine (from 43 ± 15 L/h to29 ± 11 L/h) to an extent such that these values were no longer different between the extensive and thepoor metabolizer groups. Propafenone coadministration also decreased partial metabolic clearances of mex-iletine to hydroxymethylmexiletine, p-hydroxymexiletine, and m-hydroxymexiletine in extensive metaboliz-ers by 71%, 67%, and 73%, respectively. In contrast, propafenone did not alter the kinetics of mexiletineenantiomers in subjects in the poor metabolizer group except for a slight decrease in the formation of hydroxy-methylmexiletine. Pharmacokinetic parameters of propafenone were not changed during concomitant admin-istration of mexiletine in subjects of either phenotype. Finally, electrocardiographic parameters (QRSduration, QTc, RR, and PR intervals) were not modified during the combined administration of the drugs.Conclusion: Propafenone is a potent CYP2D6 inhibitor that may cause an increase in plasma concentra-tions of coadministered CYP2D6 substrates. (Clin Pharmacol Ther 2000;67:44-57.)

Line Labbé, MSc, Gilles O’Hara, MD, Michel Lefebvre, MSc, Étienne Lessard, MSc,Marcel Gilbert, MD, Adedayo Adedoyin, PhD, Jean Champagne, MD,Bettina Hamelin, PharmD, and Jacques Turgeon, PhDSainte Foy, Quebec, Canada, and Pittsburgh, Pa

From the Quebec Heart Institute, Laval Hospital, the Faculty ofPharmacy and the Faculty of Medicine, Laval University, and theQuebec Toxicology Center, CHUQ, Sainte Foy, and the School ofPharmacy, University of Pittsburgh, Pittsburgh.

Supported by grants from the Medical Research Council of Canada(MA-12718, MT-11876, and MT-13263). Jacques Turgeon was therecipient of a scholarship from the Joseph C. Edwards Foundation.Line Labbé was the recipient of studentships from the Heart andStroke Foundation of Canada and from the Fonds pour la Formationde Chercheurs et l’Aide à la Recherche during the course of her stud-ies. Bettina Hamelin was the recipient of a scholarship from the Fondsde la Recherche en Santé du Québec. Etienne Lessard was the recip-ient of a scholarship from the Medical Research Council of Canada.

Received for publication Nov 29, 1999; accepted April 18, 2000.Reprint requests: Jacques Turgeon, PhD, Faculty of Pharmacy, Uni-

versity of Montreal, CP 6128, Succursale Centre-Ville, Montreal,Quecbec, Canada H3C 3J7.

E-mail: [email protected] © 2000 by Mosby, Inc.0009-9236/2000/$12.00 + 0 13/1/108023doi:10.1067/mcp.2000.108023

as quinidine, propafenone, disopyramide, and amio-darone has been studied and used clinically.2-5

Mexiletine undergoes stereoselective disposition inhuman beings because of an extensive metabolism; lessthan 10% of an administered oral dose is recoveredunchanged in urine.6 The major metabolites formed bycarbon and nitrogen oxidations are hydroxymethylmex-iletine, p-hydroxymexiletine, m-hydroxymexiletine,and N-hydroxymexiletine.7-9 Formation of hydroxy-methylmexiletine, p-hydroxymexiletine, and m-hydroxy-mexiletine is genetically-determined and cosegregateswith polymorphic debrisoquin 4-hydroxylase (CYP2D6)activity (Fig 1, A).8 In contrast, formation of N-hydroxy-mexiletine appears to be mediated by CYP1A2.7 Thisisozyme could play a major role in the metabolism ofmexiletine because the disposition of the drug is alteredby cigarette smoking and coadministration of ciproflox-acin.7,10 Moreover, pharmacokinetic studies have

demonstrated that mexiletine decreases clearance ofCYP1A2 substrates such as theophylline and caffeineby more than 40% because of metabolic inhibition.11,12

Propafenone is also extensively metabolized inhuman beings, with less than 1% of the dose excretedunchanged in the urine.13 Major metabolites are5-hydroxypropafenone, N-desalkylpropafenone, andpropafenone glucuronide.13 Formation of 5-hydroxy-propafenone is mediated by CYP2D6, whereas CYP1A2and CYP3A4 are involved in the formation of N-desalkylpropafenone (Fig 1, B).14,15 Propafenone is notonly extensively metabolized by CYP2D6, but it canalso inhibit the enzyme.14 The CYP2D6 inhibitory con-stant of propafenone is estimated at 50 nmol/L14 and issimilar to that of quinidine (60 nmol/L).16

Clinical data indicate that combined administration ofmexiletine and propafenone is associated with betterarrhythmia control.5 In patients in whom ventricular

Labbé et al 45CLINICAL PHARMACOLOGY & THERAPEUTICSVOLUME 68, NUMBER 1

Fig 1. Major metabolic pathways of mexiletine (A) and propafenone (B).

A

B

tachycardia could still be induced while treated withpropafenone, the tachycardia was slower, and hemody-namic deterioration requiring direct current shock wasless frequent when mexiletine was coadministered. Noattempt was made to reduce the dose of propafenonewhen mexiletine was added. Propafenone was well toler-ated by all patients before the addition of mexiletine.5

Side-effect profile of the two drugs appears improved,although no major proarrhythmic events have been clearlyassociated with the concomitant use of these drugs. Dele-terious side effects are most likely prevented by the slow,in-hospital titration of the drugs. Because both drugs aremetabolized by the same cytochrome P450 isozymes, ourstudy was designed with the following objectives: (1) todescribe the disposition of mexiletine and propafenoneunder steady-state conditions after administration ofeither drug alone and during their combined administra-tion, (2) to compare the pharmacokinetics of propafenoneand mexiletine during competitive inhibition of CYP2D6in poor metabolizers and extensive metabolizers ofCYP2D6, (3) to assess the importance of inhibitionof other cytochrome P450 isozymes (CYP1A2 andCYP3A4) on steady-state pharmacokinetics of mexile-tine and propafenone, and (4) to determine the electro-cardiographic changes during combined administrationof both antiarrhythmic agents in volunteers having dif-ferent activities of cytochrome P450 isozymes.

METHODSSubjects

Fifteen healthy men were included in the study: 4nonsmoking poor metabolizers, 4 nonsmoking exten-

sive metabolizers, 3 smoking poor metabolizers, and 4smoking extensive metabolizers of CYP2D6. Theirmean (±SD) age was 24 ± 3 years, and their mean bodyweight was 75.6 ± 10.4 kg (Table I). Among smokers,the number of cigarettes smoked per day was 22 ± 3(mean ± SD) with a range of 17 to 25. All subjects werein good health as determined by normal physical exam-ination, electrocardiography, and routine laboratory test-ing. Nobody received drugs on a regular basis. The studywas approved by the Ethics Committee for Human Sub-jects at Laval Hospital, and written informed consentwas obtained from all subjects before entry in the study.

Determination of CYP2D6 phenotypes and genotypesCYP2D6 phenotypes of volunteers participating

in this study were determined by the administrationof either debrisoquin (INN, debrisoquine) or dex-tromethorphan. The phenotype of 9 subjects was deter-mined by the debrisoquin metabolic ratio calculatedas the recovery of debrisoquin in urine to that of4-hydroxydebrisoquin.17 The ratio was calculated froman overnight urine collection after an oral administra-tion of debrisoquin hemisulfate 10 mg (Declinax;Hoffmann-LaRoche, Etobicoke, Ontario, Canada), andthe phenotype of CYP2D6 was established on the basisof an antimode of 12.6 for the metabolic ratio. Urinelevels of debrisoquin and its 4-hydroxy metabolite weredetermined by gas-liquid chromatography with flameionization detection with a DB-5 megabore column(Chromatographic Specialties, Brokville, Ontario,Canada) on the basis of an assay described previously.18

The phenotype of 6 other volunteers was established

46 Labbé et alCLINICAL PHARMACOLOGY & THERAPEUTICS

JULY 2000

Table I. Demographics and genetically determined CYP2D6 activities of volunteers

Volunteer Age (y) Weight (kg) Cigarettes/day Phenotype Genotype

1 23 96.0 — Poor metabolizer† *4/*42 27 67.3 — Poor metabolizer† *4/*43 24 68.2 — Poor metabolizer† *4/*54 20 71.4 — Poor metabolizer‡ *4/*45 21 75.0 — Extensive metabolizer‡ *1/*46 27 75.0 — Extensive metabolizer‡ *1/*17 24 83.2 — Extensive metabolizer† *1/*18 25 65.9 — Extensive metabolizer‡ *1/*19 24 81.8 20-25 Extensive metabolizer† *1/*1

10 27 63.2 25 Extensive metabolizer† *1/*111 22 72.7 20 Extensive metabolizer† *1/*112 24 77.3 17-20 Extensive metabolizer‡ NA13 30 81.4 25 Poor metabolizer† *4/*414 21 93.2 20 Poor metabolizer† *4/*415 28 71.6 25 Poor metabolizer‡ *4/*4

NA, Not available.†Phenotype determined by debrisoquin administration.‡Phenotype determined by dextromethorphan administration.

by the dextromethorphan metabolic ratio after anovernight urine collection after an oral administrationof 30 mg dextromethorphan (10 mL Balminil DM 15mg/5 mL; Rougier, Montreal, Quebec, Canada). Anantimode of 0.3 for the metabolic ratio was used todetermine the CYP2D6 phenotype. Urine concentra-tions of dextromethorphan and dextrorphan were deter-mined by a modified HPLC assay.19,20 Urine sampleswere hydrolyzed for 18 hours with β-glucuronidasetype H-1 (1 mL of 2000 U/mL solution 0.1 mol/Lsodium acetate buffer, pH 5.0) at 37°C. Saturatedsodium carbonate (1.5 mL) was added to all samples,and liquid-liquid extractions with hexane (2 × 5 mLcontaining 0.1% triethylamine) were performed.Organic phases were transferred, combined, and evap-orated to dryness under a light stream of nitrogen. Theresidue was dissolved in acetonitrile (100 µL) beforeinjection (30 µL) into the HPLC system.

The HPLC analysis was performed at ambient tem-perature with a Shimadzu system (Mandel Scientific CoLtd, Guelph, Ontario, Canada) consisting of an automaticsample injector model SIL-9A, a pump model LC-10AD, a fluorescence detector model RF-535, and anintegrator Chromatopac C-R5A. A Zorbax phenyl col-umn (250 mm × 4.6 mm, 5 µm particle size; Chromato-graphic Specialties Inc, Brockville, Ontario, Canada),and a phenyl guard column were used to perform the sep-aration. The mobile phase consisted of acetonitrile/monobasic potassium phosphate buffer 10 mmol/L at pH4.0 (60/40) containing 0.3% (vol/vol) Pic B-5 reagent.The mobile phase was pumped at a rate of 1.5 mL/min.The peaks were monitored at an excitation wavelengthof 268 nm and an emission wavelength of 310 nm.

CYP2D6 genotypes of subjects were determined bystandard polymerase chain reaction (PCR) techniques.DNA was analyzed for the presence of CYP2D6*3 andCYP2D6*4 mutant alleles according to the methoddescribed by Heim and Meyer.21 CYP2D6*5,CYP2D6*6, and CYP2D6*7 mutant alleles were deter-mined as described previously.22-24 In all subjects theirCYP2D6 genotype was in agreement with their respec-tive CYP2D6 phenotype (Table I).

Study protocolThe study was performed on 12 consecutive days.

An oral dose of mexiletine hydrochloride (Mexitil 100mg; Boehringer Ingelheim Canada Ltd., Dorval, Que-bec, Canada) was administered every 12 hours for aperiod of 8 days (day 1 to day 8). An oral dose ofpropafenone hydrochloride (Rythmol, 150 mg; KnollPharma Inc, Markham, Ontario, Canada) was alsoadministered every 12 hours, but from the morning of


day 5 to day 12. Interdose pharmacokinetic and phar-macodynamic studies were performed on the morningof day 4 (steady-state mexiletine alone), on the morn-ing of day 8 (steady-state mexiletine-propafenone), andon the morning of day 12 (steady-state propafenonealone). Forty-eight hours before and during the studyperiod, subjects abstained from other prescriptionor nonprescription drugs, vitamin supplements, caf-feine-containing beverages, foods prepared on charcoal,cruciferous vegetables, chocolate, or alcohol. On themorning of each study day, subjects were admitted tothe Clinical Research Center of Laval Hospital, and anintravenous catheter was inserted in a forearm vein.Blood samples (7 mL) were obtained before and at 0.5,1, 2, 3, 4, 5, 6, 8, 10, and 12 hours after drug adminis-tration. Blood was collected in glass tubes containingethylenediaminetetraacetic acid (Vacutainer; BectonDickinson, Franklin Lakes, NJ), and plasma was sepa-rated by centrifugation and frozen at –80°C until ana-lyzed. Heparin (66 U/mL) was used to keep the catheterpatent, and the first 3 mL of each blood sample was dis-carded. Total urine was collected over the interdoseperiod (8:00 AM to 8:00 PM). Urinary volume and pHwere recorded, and aliquots were stored at –80°C.

Plasma and urine concentrations of mexiletine andits metabolites

Plasma concentrations of mexiletine enantiomerswere measured by HPLC with fluorescence detectionafter derivatization with o-phthalaldehyde N-acetyl-L-cysteine.25 Urine concentrations of R-(–)- and S-(+)-mexiletine were determined by use of a procedure sim-ilar to that used for plasma samples.25 N-Hydroxymex-iletine is excreted as a glucuronide conjugate, which canbe hydrolyzed to mexiletine by β-glucuronidase.7,9 Thusthe urinary concentrations of N-hydroxymexiletine weredetermined as the amount of mexiletine enantiomersreleased after hydrolysis with β-glucuronidase (1000units of type H-1, from Helix Pomatia, Sigma Chemi-cal, Oakville, Ontario, Canada) for 24 hours at 37°C.

Urine concentrations of hydroxymethylmexiletine,m-hydroxymexiletine, and p-hydroxymexiletine weredetermined from aliquots after acidic hydrolysis torelease compounds from their conjugates. Two hundredfifty microliters hydrochloric acid, 4N, was added to500 µL urine samples, and hydrolysis was performedat 100°C for 30 minutes. After addition of 175 µL of4N sodium hydroxide and 750 ng venlafaxine (Wyeth-Ayerst Canada Inc, Montreal, Quebec, Canada) as inter-nal standard, urine samples were satured with sodiumchloride, and urine pH was adjusted to 9.7 ± 0.1 withcarbonate-bicarbonate buffer, 1 mL (1 mol/L), at pH 9.7

and 1N hydrochloric acid. Then liquid-liquid extractionwith two 5-mL portions of diethylether was performed.The organic phases were combined and evaporated todryness under a light stream of nitrogen. The residueobtained was dissolved in 150 µL tetrahydrofuran.Derivatization was carried out at 65°C after sequentialaddition of two reagents: (1) N-methyl-N-(trimethylsi-lyl)trifluoroacetamide, 30 µL, and (2) 70 minutes later,N-methyl-bis(trifluoroacetamide), 30 µL. Derivatiza-tion was allowed to come to completion (70 minutes)before evaporation. The residue was resuspended in150 µL distilled diethylether, and 1 µL was analyzedby gas chromatography–mass spectrometry.

Gas chromatography–mass spectrometry analyseswere carried out with a Hewlett Packard 6890 gas chro-matograph combined with a Hewlett Packard 5973 massspectrometer (Hewlett Packard Ltd, Kirkland, Quebec)operating at an ionization potential of 70 eV. Sampleswere injected in a splitless mode (injection port tempera-ture was 250°C) with an HP-5MS (30 m × 0.25 mm innerdiameter, 0.25 µm film thickness) capillary column(Hewlett Packard Ltd). Initial oven temperature was setat 125°C for 1 minute followed by an increase of2.6°C/min until a temperature of 200°C was reached.Then oven temperature was increased at a rate of30°C/min up to a final temperature of 285°C. Helium wasused as carrier gas at a rate of 1 mL/min. Temperaturesof the transfer line and of the ionization source were280°C and 230°C, respectively. Data acquisition was per-formed with the HP ChemStation software (HewlettPackard Ltd), whereas peak identification and quantifica-tion were achieved by use of the selected ion monitoringmode. For p-hydroxymexiletine and m-hydroxymexile-tine derivatives, m/z 210 was selected, whereas m/z 120and m/z 58 were monitored for hydroxymethylmexiletineand venlafaxine, respectively.

Plasma and urine concentrations of propafenoneand its metabolites

Plasma concentrations of propafenone, 5-hydroxy-propafenone, and N-desalkylpropafenone were deter-mined by a modified HPLC method.26 In brief, 25 µL(250 ng) of an aqueous solution of the internal standardLU 55086 (BASF Pharma Knoll, Ludwigshafen, Ger-many) and 300 µL of 0.1 mol/L borate buffer pH 9 wereadded to plasma 0.5 mL. Liquid-liquid extraction withtwo fractions of 5 mL of diethylether was performed. Theorganic phases were combined and concentrated to about1 mL in a water bath at 45°C. Then 0.05N sulfuric acid,150 µL, was added, and the mixture was shaken for 1minute. The phases were separated by centrifugation for10 minutes, and the ether phase was discarded. The remain-

ing acid phase was washed again with 1 mL diethylether,and 50 µL was injected into the HPLC system.

Urine concentrations of propafenone and its twometabolites were determined from aliquots before andafter enzymatic hydrolysis to release compounds fromtheir conjugates. For hydrolysis, urine samples (200µL) were mixed with 0.5 mL of 0.1 mol/L acetate bufferpH 5 containing 1000 units of β-glucuronidase (typeH-1, from Helix Pomatia, Sigma Chemical, Oakville,Ontario, Canada), and the hydrolysis was conducted at37°C for 24 hours. Urine samples were extracted asdescribed for plasma samples, except that urine, 200µL, borate buffer (0.1 mol/L) 1.5 mL, and the internalstandard LU 55086, 3 µg, were used.

The solvent delivery system was a Shimadzu pumpmodel LC-6A, and the sample injections were per-formed with a Shimadzu SIL-9A autosampler (MandelScientific Co Ltd). The analytical column was a Beck-mann Ultrasphere ODS (250 mm × 4.6 m, 5 µm parti-cle size; Beckmann, Montreal, Quebec, Canada), andthe column effluent was monitored with an ultravioletdetector (detector model 441, Canada Waters Ltd, Mis-sissauga, Ontario) at 254 nm. The mobile phase was amixture of triethylamine (0.02 mol/L) in H2SO4(0.03N), acetonitrile, and methanol (635:275:90vol/vol). The flow rate was set at 1.5 mL/min.

Data analysisNoncompartmental analysis was performed to deter-

mine oral, renal, and nonrenal clearances of mexiletineand propafenone, as well as to evaluate partial meta-bolic clearances of the drugs (mexiletine andpropafenone) to their various metabolic pathways.Whenever possible, stereoselective pharmacokineticparameters were determined for mexiletine. The areaunder the plasma concentration versus time curve dur-ing the 12-hour dosing interval [AUC(0-τ)] was deter-mined by use of the trapezoidal and log-trapezoidalrules for ascending and descending data, respectively.27

Oral clearance (CLoral) was calculated as

Dose of the drug (base form)over a dosing interval/AUC(0-τ) of the drug

Renal clearance (CLR) was calculated as the ratio of theamount of unchanged drug excreted over the dosinginterval to the AUC(0-τ) of this drug. Nonrenal clear-ance of mexiletine enantiomers was determined by sub-tracting the renal clearance from the systemic clearance(F × CLoral) of each enantiomer where the bioavailabil-ity (F) was fixed at 0.9.28 Partial metabolic clearancesof either mexiletine or propafenone to their differentmetabolites were determined as [Aemet/AUC0-τ)] where


JULY 2000

Aemet is the amount of each metabolite excreted in urineover a dosing interval. For this calculation, the amountof the metabolites, as well as AUC of the parent drugwas expressed in molar units.29

Electrocardiographic measurementsElectrocardiographic measurements at screening and

throughout the study were obtained as vectocardio-graphic electrocardiograms where X (coronal), Y (lat-eral), and Z (sagittal) leads were recorded at a paperspeed of 25 or 50 mm/sec at baseline (no drug) and atspecific times (0, 2, and 12 hours) after drug adminis-tration. Determination of cycle lengths (RR intervals),QRS, PR, and QT intervals was done by a single indi-vidual, manually with the help of a digitized tablet(Summa-Sketch II+, Summagraphics, Seymour, Conn).The QT, QRS, and RR intervals were determined dur-ing at least three consecutive beats, whereas two con-secutive beats were used to average the PR intervals.The end of the T wave was identified as the interceptof the isoelectric signal and a line tangential to the pointof maximum T wave slope (“slope intercept”).30 QTintervals were corrected for heart rate according toBazett’s formula31:

QTc = QT/RR1⁄2

Statistical analysis

Normality and variance assumption were tested withthe Shapiro-Wilk test and Bartlett’s statistics. Data wereanalyzed to determine effects of comedication, enan-tiomer (for mexiletine only), phenotype, and cigarettesmoking on the pharmacokinetics of mexiletine orpropafenone. Data were compared by use of a random-ized block design, a split-plot design, and a split-split-plot design. The electrocardiographic data (QRS, QTc,RR, and PR intervals) at baseline and at three specifictimes during administration of the drugs alone ortogether were compared by use of ANOVA. All reportedP values are two-sided, and the Fisher’s F test was usedon nontransformed data because we did not observe anystatistical evidence to reject the variance assumptions.The results were considered significant if P values wereless than .05. The data were analyzed with the statisti-cal package SAS (SAS Institute Inc, Cary, NC).

RESULTSPharmacokinetics of mexiletine in extensive metab-olizers and poor metabolizers

The plasma concentrations of mexiletine enan-tiomers after oral administration of mexiletine alone(open circles) in one poor metabolizer subject (upper

panel) and one extensive metabolizer subject (lowerpanel) are shown in Fig 2. Mean plasma concentrationsof both R-(–)- and S-(+)-mexiletine were higher inplasma of the poor metabolizer than in plasma of theextensive metabolizer subject. The mean values ofAUC(0-12) for all subjects studied were 1.7 ± 0.5 µg ·h/mL for R-(–)-mexiletine and 1.5 ± 0.4 µg · h/mL forS-(+)-mexiletine in poor metabolizers and 1.1 ± 0.3µg · h/mL for R-(–)-mexiletine and 1.1 ± 0.4 µg · h/mLfor S-(+)-mexiletine in extensive metabolizers (P < .05;extensive metabolizers versus poor metabolizers forboth enantiomers). The solid circles in Fig 2 representplasma concentrations of mexiletine enantiomersmeasured during the concomitant administration ofpropafenone and mexiletine in the same poor metabolizerand extensive metabolizer subjects. Coadministration ofpropafenone did not alter the plasma concentrationsof R-(–)- or S-(+)-mexiletine in the poor metabolizersubject. In contrast, the mean plasma concentrations[AUC(0-12)] of both enantiomers were increased by


Fig 2. Semilog plots of plasma concentrations of R-(–)-mex-iletine (left panels) and S-(+)-mexiletine (right panels) inrepresentative subjects with either the poor (upper panels)or the extensive (lower panels) metabolizer phenotypes aftermexiletine alone (open circles) and mexiletine pluspropafenone (solid circles).

propafenone in the extensive metabolizer. Overall,mean AUC(0-12) of R-(–)-mexiletine and S-(+)-mexiletine increased to 1.6 ± 0.4 µg · h/mL and 1.6 ±0.6 µg · h/mL in extensive metabolizers during the con-comitant administration of propafenone (both P < .05versus mexiletine alone).

Pharmacokinetic parameters of mexiletine enan-tiomers observed in extensive metabolizers and poormetabolizers during mexiletine alone and during the con-comitant administration of propafenone are reported inTable II. After administration of mexiletine alone, meanoral clearances of both R-(–)- and S-(+)-mexiletine wereincreased 1.6- and 1.5-fold, respectively, in extensivemetabolizers compared with poor metabolizers (P < .05).A similar extent of increase was noted for the nonrenalclearance of each enantiomer. Coadministration ofpropafenone to extensive metabolizers significantlydecreased the oral and nonrenal clearances of bothR-(–)- and S-(+)-mexiletine to values similar to those mea-sured in poor metabolizers. In contrast, coadministrationof propafenone did not affect the oral and nonrenal clear-ances of mexiletine enantiomers in poor metabolizers(P > .05; Table II). The renal clearances of R-(–)- andS-(+)-mexiletine were similar in extensive metabolizersand in poor metabolizers after mexiletine alone and werenot affected by the coadministration of propafenone.

The urinary recovery of mexiletine enantiomers asN-hydroxymexiletine glucuronide and the partial meta-bolic clearances of R-(–)- and S-(+)-mexiletine toN-hydroxymexiletine glucuronide were highly stereo-selective in both phenotypes; the R/S ratios were 24 ± 6

for the urinary recovery and 24 ± 8 for partial metabolicclearance in extensive metabolizers whereas in poormetabolizers the ratios were 24 ± 15 for the urinary recov-ery and 22 ± 15 for partial metabolic clearance. Co-administration of propafenone did not significantly alterthe R/S ratio of these parameters in subjects with eitherphenotype (23 ± 6 in extensive metabolizers and 31 ± 21in poor metabolizers for the urinary recovery and 23 ± 7in extensive metabolizers and 29 ± 17 in poor metaboliz-ers for the partial metabolic clearance). Urinary recoveryof N-hydroxymexiletine was higher in poor metabolizersthan in extensive metabolizers (Table II). Coadministra-tion of propafenone increased urinary recovery ofN-hydroxymexiletine in extensive metabolizers to levelssimilar to those observed in poor metabolizers. Neverthe-less, the partial metabolic clearances of mexiletine enan-tiomers to N-hydroxymexiletine glucuronide were alwayssimilar between extensive metabolizers and poor metab-olizers and were unaltered by propafenone coadministra-tion in subjects of either phenotype (Table II).

The partial metabolic clearances of mexiletine tohydroxymethylmexiletine, m-hydroxymexiletine, andp-hydroxymexiletine were increased 4.7-, 4.2-, and 6.8-fold, respectively, in extensive metabolizers comparedwith poor metabolizers after the administration of mex-iletine alone (Table III and Fig 3). Coadministration ofpropafenone to extensive metabolizers decreased by 71%,67%, and 73% the partial metabolic clearances of mexile-tine to hydroxymethylmexiletine, m-hydroxymexiletine,and p-hydroxymexiletine, respectively. In contrast, in poormetabolizers, only the partial metabolic clearance of mex-


JULY 2000

Table II. Pharmacokinetic parameters of mexiletine enantiomers in extensive and poor metabolizers before andduring propafenone coadministration

Extensive metabolizers (n = 8) Poor metabolizers (n = 7)

R-(–)-Mexiletine S-(+)-Mexiletine R-(–)-Mexiletine S-(+)-Mexiletine

Mexiletine Mexiletine + Mexiletine Mexiletine + Mexiletine Mexiletine + Mexiletine Mexiletine +alone propafenone alone propafenone alone propafenone alone propafenone

CLoral (L/h) 41 ± 11 28 ± 7* 43 ± 15 29 ± 11* 26 ± 7† 26 ± 7 29 ± 8† 28 ± 9CLR (L/h) 1.8 ± 0.9 2.5 ± 2.7 2.1 ± 1.0 2.9 ± 3.1 1.8 ± 1.1 2.1 ± 1.6 2.1 ± 1.2 2.4 ± 1.8CLNR (L/h) 35 ± 10 23 ± 6* 36 ± 14 23 ± 9* 22 ± 6† 21 ± 7 24 ± 7† 22 ± 8CLMex→NOH (L/h)§ 10 ± 2 11 ± 2 0.5 ± 0.2‡ 0.5 ± 0.2‡ 11 ± 4 11 ± 4 0.7 ± 0.5‡ 0.6 ± 0.4‡Urinary recovery (% of the dose)�

Mexiletine 5 ± 4 9 ± 10* 6 ± 5 11 ± 15* 7 ± 4 9 ± 7* 7 ± 4 10 ± 7*N-Hydroxymexiletine 26 ± 7 41 ± 12* 0.9 ± 0.4‡ 1.5 ± 1.0*‡ 40 ± 8† 43 ± 10 2.3 ± 1.5†‡ 2.0 ± 1.2‡

Data are mean values ± SD.*P < .05 mexiletine plus propafenone versus mexiletine alone.†P < .05 poor metabolizers versus extensive metabolizers.‡P < .05 S-(+)-mexiletine versus R-(–)-mexiletine.§Partial metabolic clearance of mexiletine to N-hydroxymexiletine.�Urinary recovery of specific enantiomer in 12-hour urine collection.

iletine to hydroxymethylmexiletine was significantlydecreased by the administration of propafenone.

Pharmacokinetics of mexiletine in smokers andnonsmokers

After administration of mexiletine alone, areas underplasma concentration–time curve of mexiletine enan-tiomers were significantly higher in nonsmokers [1.6 ±0.5 µg · h/mL for R-(–)-mexiletine and 1.6 ± 0.4 µg ·h/mL for S-(+)-mexiletine] compared with smokers[1.1 ± 0.3 µg · h/mL for R-(–)-mexiletine and 1.0 ± 0.3µg · h/mL for S-(+)-mexiletine]. Moreover, oral andnonrenal clearances of mexiletine enantiomers were


1.5- to 1.7-fold higher in smokers than in nonsmokers,independently of CYP2D6 phenotype of the subjects(P < .05; Table IV). Coadministration of propafenonesignificantly decreased the oral clearance of mexiletinein smokers [9 L/h for R-(–)-mexiletine and 11 L/h forS-(+)-mexiletine] and in nonsmokers [5 L/h for R-(–)-mexiletine and 5 L/h for S-(+)-mexiletine; Table IV].In both groups, partial metabolic clearances of mexile-tine to hydroxymethylmexiletine, m-hydroxymexile-tine, and p-hydroxymexiletine were significantlydecreased, whereas partial metabolic clearance of mex-iletine to N-hydroxymexiletine was not altered bypropafenone coadministration (Table III and Table IV).

Fig 3. Mexiletine partial metabolic clearances to hydroxymethylmexiletine (CLMex→OHMEX, leftpanel), m-hydroxymexiletine (CLMex→MOH, middle panel), and p-hydroxymexiletine (CLMex→POH,right panel) in individual extensive metabolizers (open circles) and poor metabolizers (solid cir-cles) after mexiletine alone (Mex) and mexiletine plus propafenone (Mex + Pro). *P < .05 mexile-tine plus propafenone versus mexiletine alone in extensive metabolizers. †P < .05 mexiletine pluspropafenone versus mexiletine alone in poor metabolizers.

Table III. Recovery urinary and partial metabolic clearances of mexiletine to CYP2D6-dependent metabolicpathways in extensive metabolizer, poor metabolizer, smoking, and nonsmoking groups

Extensive metabolizers Poor metabolizers Smokers Nonsmokers(n = 8) (n = 7) (n = 7) (n = 8)

Mexiletine + Mexiletine + Mexiletine + Mexiletine +Mexiletine propafenone Mexiletine propafenone Mexiletine propafenone Mexiletine propafenone

Partial metabolic clearance of mexiletine to (L/h)Hydroxymethylmexiletine 4.7 ± 2.4 1.4 ± 0.6* 1.0 ± 0.3† 0.7 ± 0.2*† 3.3 ± 2.4 1.3 ± 0.7* 2.6 ± 2.9 0.9 ± 0.3*m-Hydroxymexiletine 0.8 ± 0.3 0.3 ± 0.1* 0.2 ± 0.1† 0.1 ± 0.1 0.6 ± 0.5 0.3 ± 0.1* 0.4 ± 0.3 0.2 ± 0.1*p-Hydroxymexiletine 1.8 ± 0.8 0.5 ± 0.3* 0.3 ± 0.1† 0.2 ± 0.1† 1.4 ± 1.1 0.5 ± 0.3* 0.8 ± 0.8 0.3 ± 0.1*

Urinary recovery (% of the dose)‡Hydroxymethylmexiletine 11.2 ± 4.4 4.8 ± 1.4* 3.6 ± 0.8† 2.7 ± 0.7*† 7.0 ± 4.0 3.8 ± 1.9* 8.2 ± 6.0 3.8 ± 1.3*m-Hydroxymexiletine 1.8 ± 0.6 0.9 ± 0.3* 0.7 ± 0.4† 0.6 ± 0.3 1.3 ± 0.9 0.8 ± 0.4* 1.3 ± 0.7 0.7 ± 0.3*p-Hydroxymexiletine 4.4 ± 1.4 1.8 ± 0.7* 1.0 ± 0.4† 0.7 ± 0.2† 3.0 ± 2.2 1.5 ± 0.9* 2.7 ± 2.0 1.1 ± 0.5*

Data are mean values ± SD.*P < .05 mexiletine plus propafenone versus mexiletine alone.†P < .05 poor metabolizers versus extensive metabolizers.‡Urinary recovery in 12-hour urine collection.

Pharmacokinetics of propafenone in extensivemetabolizers and poor metabolizers

Pharmacokinetic parameters of propafenone beforeand during mexiletine administration in extensive


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metabolizer and poor metabolizer subjects are shownin Table V. After administration of propafenone alone,significant differences in the pharmacokinetics ofpropafenone were observed between extensive metab-

Table IV. Pharmacokinetic parameters of mexiletine enantiomers in smokers and nonsmokers before and duringpropafenone coadministration

Smokers (n = 7) Nonsmokers (n = 8)

R-(–)-Mexiletine S-(+)-Mexiletine R-(–)-Mexiletine S-(+)-Mexiletine

Mexiletine + Mexiletine + Mexiletine + Mexiletine +Mexiletine propafenone Mexiletine propafenone Mexiletine propafenone Mexiletine propafenone

CLoral (L/h) 41 ± 11 32 ± 6* 46 ± 12 35 ± 8* 28 ± 9† 23 ± 5*† 28 ± 8† 23 ± 6*†CLR (L/h) 1.3 ± 0.8 1.9 ± 2.7 1.6 ± 0.9 2.2 ± 2.9 2.2 ± 0.9 2.6 ± 1.7 2.5 ± 1.0 3.1 ± 2.1CLNR (L/h) 36 ± 10 27 ± 4* 40 ± 11 29 ± 5* 23 ± 8† 18 ± 5*† 23 ± 8† 17 ± 6*†CLMex→NOH (L/h)§ 11 ± 4 12 ± 3 0.8 ± 0.4‡ 0.6 ± 0.3‡ 9 ± 2 10 ± 3 0.4 ± 0.2‡ 0.4 ± 0.3‡Urinary recovery (% of the dose)�

Mexiletine 3.4 ± 2.1 5.3 ± 6.8* 3.6 ± 2.3 5.2 ± 5.8* 8.1 ± 3.0† 12.0 ± 8.9*† 9.5 ± 3.9† 14.9 ± 13.4*†N-Hydroxymexiletine 30 ± 14 39 ± 8* 2.0 ± 1.6‡ 1.9 ± 0.9‡ 34 ± 6 45 ± 12* 1.3 ± 0.7‡ 1.8 ± 1.2‡

Data are mean values ± SD.*P < .05 mexiletine plus propafenone versus mexiletine alone.†P < .05 nonsmokers versus smokers.‡P < .05 S-(+)-mexiletine versus R-(–)-mexiletine.§Partial metabolic clearance of mexiletine to N-hydroxymexiletine.�Urinary recovery of specific enantiomer in 12-hour urine collection.

Table V. Pharmacokinetic parameters of propafenone in extensive metabolizer, poor metabolizer, smoking, ornonsmoking groups before and during mexiletine coadministration

Extensive metabolizers Poor metabolizers Smokers Nonsmokers(n = 8) (n = 7) (n = 7) (n = 8)

Propafenone + Propafenone + Propafenone + Propafenone +Propafenone mexiletine Propafenone mexiletine Propafenone mexiletine Propafenone mexiletine

CLoral (L/h) 246 ± 134 288 ± 180 31 ± 11* 29 ± 10* 179 ± 154 214 ± 226 116 ± 142 127 ± 143CLR (L/h) 0.3 ± 0.2 0.4 ± 0.3 0.3 ± 0.2 0.3 ± 0.2 0.2 ± 0.1 0.3 ± 0.3 0.3 ± 0.2 0.4 ± 0.3CLPro→5OH (L/h)‡ 43 ± 19 54 ± 28 1.6 ± 2.0* 1.1 ± 1.7* 29 ± 28 33 ± 35 19 ± 24 26 ± 34CLR5OH (L/h)§ 4.1 ± 1.1 4.2 ± 1.6 4.8 ± 2.8 3.4 ± 2.3 4.2 ± 1.1 3.6 ± 1.4 4.5 ± 2.4 4.0 ± 2.3CLPro→Ndes (L/h)� 12 ± 7 15 ± 9 1.5 ± 0.3* 1.6 ± 0.3* 9 ± 9 11 ± 11 5 ± 6 7 ± 8CLRNdes (L/h)¶ 2.1 ± 0.5 2.3 ± 1.0 2.3 ± 1.2 2.0 ± 1.0 2.1 ± 0.6 2.1 ± 0.9 2.3 ± 1.1 2.3 ± 1.0CLPro→Pro conjugate(L/h)# 16 ± 7 20 ± 10 9 ± 2* 8 ± 3* 16 ± 7 17 ± 10 10 ± 4 11 ± 9Urinary recovery (% of the dose)**

Propafenone alone 0.1 ± 0.1 0.2 ± 0.1 1.1 ± 0.9* 1.0 ± 1.0* 0.3 ± 0.3 0.2 ± 0.2 0.8 ± 1.0 0.8 ± 1.0Conjugated propafenone 8 ± 2 8 ± 3 30 ± 5* 27 ± 4* 15 ± 10 15 ± 10 20 ± 14 18 ± 115-Hydroxypropafenone 1.2 ± 0.4 1.2 ± 0.4 0.2 ± 0.1* 0.1 ± 0.1* 0.7 ± 0.5 0.7 ± 0.5 0.8 ± 0.7 0.7 ± 0.7

aloneConjugated 18 ± 3 19 ± 5 4 ± 5* 3 ± 5* 12 ± 7 12 ± 7 10 ± 9 12 ± 12

5-hydroxypropafenoneN-Desalkylpropafenone 0.2 ± 0.1 0.3 ± 0.2† 1.1 ± 0.6* 1.4 ± 0.9*† 0.3 ± 0.3 0.4 ± 0.3 0.9 ± 0.8 1.1 ± 1.0

aloneConjugated 5 ± 1 5 ± 1 4 ± 1 4 ± 1 4 ± 1 4 ± 1 4 ± 1 5 ± 1

N-desalkylpropafenone

Data are mean values ± SD.*P < .05 poor metabolizers versus extensive metabolizers.†P < .05 propafenone plus mexiletine versus propafenone alone.‡Partial metabolic clearance of propafenone to 5-hydroxypropafenone.§Renal clearance of 5-hydroxypropafenone.�Partial metabolic clearance of propafenone to N-desalkylpropafenone.¶Renal clearance of N-desalkylpropafenone.#Partial metabolic clearance of propafenone to its conjugate.**Urinary recovery in 12-hour urine collection.

olizers and poor metabolizers. In fact, AUC(0-12)values of propafenone and of N-desalkylpropafenonewere significantly higher, whereas AUC(0-12) of5-hydroxypropafenone was significantly lower in poormetabolizers (14 ± 5 nmol · h/mL for propafenone,0.2 ± 0.2 nmol · h/mL for 5-hydroxypropafenone, and2.0 ± 1.1 nmol · h/mL for N-desalkylpropafenone)compared with extensive metabolizers (2 ± 1 nmol ·h/mL for propafenone, 1.2 ± 0.3 nmol · h/mL for5-hydroxypropafenone, and 0.4 ± 0.3 nmol · h/mL forN-desalkylpropafenone). Consequently, mean oralclearance of propafenone was 8-fold higher in exten-sive metabolizers compared with poor metabolizersafter administration of the drug alone (P < .05; TableV). In addition, partial metabolic clearance of propa-fenone to 5-hydroxypropafenone was increased 27-foldin extensive metabolizers compared with poor metabo-lizers (P < .05). Furthermore, the partial metabolicclearance of propafenone to N-desalkylpropafenonealso appeared increased in extensive metabolizers. Incontrast, no difference was observed for the renal clear-ance between the two phenotypes. Finally, coadministra-tion of mexiletine did not alter any of the pharmacokineticparameters of propafenone in either phenotype.

Pharmacokinetics of propafenone in smokers andnonsmokers

No differences in the pharmacokinetic parametersof propafenone were noted between smokers and non-smokers after administration of propafenone alone(Table V). However, oral clearance of propafenonetended to be greater (1.5-fold) in smokers comparedwith nonsmokers. Similarly, partial metabolic clear-ances of propafenone to 5-hydroxypropafenone andto N-desalkylpropafenone tended to be increased by1.5- and 1.8-fold, respectively, in smokers comparedwith nonsmokers. Mexiletine coadministration hadno significant impact on the pharmacokinetic param-eters of propafenone, neither in smokers nor in non-smokers.

Electrocardiographic dataFig 4 illustrates mean electrocardiographic parame-

ters (QRS, QTc, RR, and PR) in all subjects measuredat three specific times (0, 2, and 12 hours) after admin-istration of the drugs either alone or together. Two hoursafter dosing, QRS intervals were lower during adminis-tration of mexiletine alone than during propafenonealone or propafenone plus mexiletine (P < .05). More-over, RR intervals at the expected peak plasma concen-tration of the drugs were longer, whereas QTc intervalswere shorter compared with the two other times mea-

sured (P < .05). Electrocardiographic intervals measured2 hours after drug administration were also analyzedtaking into account CYP2D6 phenotype and smokingstatus (Table VI). These two variables had very littleimpact on the pattern of effects observed. Administra-tions of mexiletine or propafenone were associated withsignificant changes in QTc and RR intervals comparedwith baseline in most groups of subjects. Coadminis-tration of mexiletine with propafenone led to a differ-ent extent of QRS widening and RR prolongation thanon mexiletine alone. On the other hand, only the QTcinterval appeared shorter during the combined admin-istration of mexiletine and propafenone compared withpropafenone alone. Overall, all changes in electrocar-diographic parameters were of minor amplitude in allgroups of subjects.


Fig 4. QRS (top left), QTc (top right), RR (bottom left),and PR (bottom right) intervals (mean ± SD) measured atspecific times (0, 2, and 12 hours) after administration ofmexiletine alone (circles), mexiletine plus propafenone(squares), and propafenone alone (inverted triangles) in allsubjects. Time 0 represents time of dose administration onthe morning of the 3 study days.

DISCUSSION

Concomitant administration of propafenone signifi-cantly impaired elimination of mexiletine primarilybecause of inhibition of CYP2D6 activity. In extensivemetabolizers propafenone inhibited the formation ofthe three major metabolites of mexiletine, namelyhydroxymethylmexiletine, p-hydroxymexiletine, andm-hydroxymexiletine; all of them were dependent ofCYP2D6 activity. Consequently, differences in mexile-tine pharmacokinetics between phenotypes were almostabsent after addition of propafenone. On the other hand,none of the pharmacokinetic parameters of propafenonewere modified during the concomitant administrationof mexiletine.

Pharmacokinetics of mexiletineThe role of debrisoquin polymorphism in the dispo-

sition of mexiletine is well known. In fact we havedemonstrated that formation of hydroxymethylmexile-tine, p-hydroxymexiletine, and m-hydroxymexiletinebut not N-hydroxymexiletine is mediated by the poly-morphic CYP2D6 enzyme.8 Similar results wereobtained in this study where mexiletine oral clearance,nonrenal clearance, and partial metabolic clearances tohydroxymethylmexiletine, p-hydroxymexiletine, and

m-hydroxymexiletine were higher in extensive metab-olizer subjects compared with poor metabolizers.

Propafenone coadministration treatment selectivelyaltered the disposition of mexiletine enantiomers in exten-sive metabolizers. In these latter subjects, addition ofpropafenone increased the mean plasma concentrations ofboth R-(–)- and S-(+)-mexiletine while decreasing mex-iletine oral clearance, mexiletine nonrenal clearance, andpartial metabolic clearances of mexiletine to hydroxy-methylmexiletine, p-hydroxymexiletine, and m-hydroxy-mexiletine. After addition of propafenone, pharmacoki-netic parameters of mexiletine in extensive metabolizerswere modified to an extent such that differences were mostabsent between extensive metabolizers and poor metabo-lizers. In contrast to extensive metabolizers, propafenonecoadministration to poor metabolizers had no effect onmexiletine pharmacokinetics except for the formation ofhydroxymethylmexiletine. These results suggest selectiveinhibition of CYP2D6-mediated metabolism of mexile-tine by propafenone. Propafenone has also been shown toalter the disposition of other CYP2D6 substrates.32,33

Formation of hydroxymethylmexiletine was signifi-cantly altered by the administration of propafenone inpoor metabolizer subjects. Although the formation ofhydroxymethylmexiletine is mediated by CYP2D6, other


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Table VI. Electrocardiographic intervals at baseline (without drugs) and at the expected peak plasma concentrationof mexiletine alone, mexiletine plus propafenone, and propafenone alone in extensive metabolizer, poor metabolizer,smoking, and nonsmoking groups

At 2 hours after administration of the drugs

Intervals Mexiletine Mexiletine + Propafenone(msec) Subject Baseline alone propafenone alone

QRS Extensive metabolizers of CYP2D6 (n = 8) 98 ± 10 91 ± 10* 102 ± 11† 100 ± 12†Poor metabolizers of CYP2D6 (n = 7) 87 ± 11‡ 88 ± 6 95 ± 9‡ 98 ± 10Smokers (n = 7) 92 ± 11 88 ± 10 97 ± 12† 96 ± 10†Nonsmokers (n = 8) 101 ± 7 94 ± 6 100 ± 10† 101 ± 11†

QTc Extensive metabolizers of CYP2D6 (n = 8) 378 ± 21 358 ± 20* 365 ± 23* 371 ± 31*†§Poor metabolizers of CYP2D6 (n = 7) 396 ± 19 369 ± 13* 364 ± 17* 374 ± 27*†§Smokers (n = 7) 385 ± 19 360 ± 21* 372 ± 25* 373 ± 20†§Nonsmokers (n = 8) 376 ± 24 362 ± 18* 358 ± 13* 373 ± 35†§

RR Extensive metabolizers of CYP2D6 (n = 8) 905 ± 214 1083 ± 173* 986 ± 178*† 94 ± 170*†Poor metabolizers of CYP2D6 (n = 7) 905 ± 124 1058 ± 159* 984 ± 138*† 1001 ± 141*†Smokers (n = 7) 831 ± 115 1005 ± 163* 915 ± 162*† 923 ± 156*†Nonsmokers (n = 8) 1019 ± 210� 1155 ± 131*� 1063 ± 122*†� 1086 ± 100*†�

PR Extensive metabolizers of CYP2D6 (n = 8) 107 ± 27 121 ± 21 128 ± 26 134 ± 29*Poor metabolizers of CYP2D6 (n = 7) 114 ± 26 110 ± 18 109 ± 20‡ 112 ± 25‡Smokers (n = 7) 115 ± 28 122 ± 20 125 ± 31 126 ± 35Nonsmokers (n = 8) 106 ± 25 111 ± 19 114 ± 15 122 ± 24

Values are reported as mean ± SD.*P < .05 versus baseline.†P < .05 versus mexiletine alone.‡P < .05 poor metabolizers versus extensive metabolizers.§P < .05 versus mexiletine plus propafenone.�P < .05 nonsmokers versus smokers.

isozymes appear involved in this metabolic pathway. Infact, formation of this metabolite is impaired but not pre-vented in poor metabolizers and was partially abolishedby quinidine coadministration in extensive metabolizers.8

In vitro studies with human liver microsomes have shownthat formation of hydroxymethylmexiletine was stronglyreduced but not completely abolished by several CYP2D6substrates, by quinidine, and by an antibody direct againstCYP2D6.34,35 In addition, it was recently reported thatmexiletine parahydroxylation and methylhydroxylationare catalyzed partially by CYP1A2.36 Finally, in a previ-ous study we have also observed that the formation ofthis metabolite was increased by cigarette smoking (aknown inducer of CYP1A2).7,37

We have recently used inhibition and induction ofCYP1A2 to demonstrate a role of CYP1A2 in the metab-olism of mexiletine in humans.10 Ciprofloxacin, a knowninhibitor of CYP1A2 activity,38 decreased clearances ofR-(–)-mexiletine and S-(+)-mexiletine by 8% and 15% to21%, respectively, whereas clearances of R-(–)-mexiletineand S-(+)-mexiletine were 42% and 63% higher in smok-ers compared with nonsmokers. Similar observations weremade in this study. The mean concentrations of mexile-tine enantiomers were significantly lower in smokers thannonsmokers, whereas the oral clearances of R-(–)-mexile-tine and S-(+)-mexiletine were 1.5 to 1.7 higher in thesmokers. However, our data suggest that propafenone didnot cause a noticeable inhibition of CYP1A2 activity. Nosignificant modification of mexiletine pharmacokineticswas observed after coadministration of propafenone,particularly in poor metabolizers, who would be most sen-sitive to CYP1A2 inhibition. Limited inhibition of mex-iletine metabolism by propafenone could be explained bya Ki of propafenone for inhibition of CYP1A2 much largerthan the Km of mexiletine for this isozyme.

Changes in mexiletine AUCs noticed especially inextensive metabolizers during the concomitant admin-istration of propafenone could be related to a modifi-cation in its absorption phase. Propafenone is knownto inhibit the P-glycoprotein.39 A slight increase in theoverall urinary recovery of mexiletine and its metabo-lites noticed in poor metabolizers during concomitantadministration of propafenone may be indicative ofP-glycoprotein–mediated transport inhibition. On theother hand, oral clearance data in poor metabolizers donot support this hypothesis because no changes in thisparameter were observed during concomitant adminis-tration of mexiletine and propafenone.

Pharmacokinetics of propafenoneBioavailability of propafenone after oral administra-

tion is low because of extensive first-pass metabolism.


Moreover, large interindividual variability in propa-fenone plasma concentrations is observed and isexplained by a drug metabolism largely dependent onCYP2D6 activity.14 In this study, after administration ofpropafenone alone, the areas under the plasma concen-tration–time curve were 7-fold higher for propafenoneand 6-fold lower for 5-hydroxypropafenone in poormetabolizers compared with extensive metabolizers. Inaddition, oral clearance of propafenone and partial meta-bolic clearance of propafenone to 5-hydroxypropafenonewere increased by 8- and 27-fold in extensive metabo-lizer subjects. Coadministration of mexiletine did notalter the pharmacokinetics of propafenone either inextensive metabolizer or in poor metabolizer subjects.

In vitro studies have demonstrated that the N-dealkyl-ation of propafenone is mediated by CYP3A4 andCYP1A2.15 Moreover, case reports suggest the impli-cation of these two isozymes in the metabolism ofpropafenone.40-42 To better study the role of CYP1A2on the metabolism of propafenone, we compared phar-macokinetic parameters of the drug in smokers andnonsmokers. Area under plasma concentration–timecurve of propafenone tended to be smaller in smokers,whereas oral clearance of the drug was 1.5-fold higherin smokers compared with nonsmokers. These findingsmay suggest an implication of CYP1A2 in propafenonemetabolism, although the difference did not reach sta-tistical significance. Larger studies are needed to deter-mine the exact role of this isozyme in the dispositionof propafenone in human beings.

Electrocardiographic dataMexiletine, a class Ib antiarrhythmic agent, blocks the

voltage-dependent fast sodium channel with a fast rate ofdissociation.43 In contrast, propafenone is a class Ic antiar-rhythmic agent which possesses a slow rate of dissocia-tion from the sodium channel.44 These differences explainwhy at usual heart rates, little accumulation of block isobserved with mexiletine compared with propafenone.This usually translates into more significant prolongationof QRS intervals by propafenone than by mexiletine.In the present study, significant widening of the QRSintervals was noticed only during administration ofpropafenone. Addition of mexiletine to propafenone didnot lead to further changes in this electrocardiographicparameter.

Propafenone also exhibits β-blocking,45 calciumchannel,45,46 and potassium channel–blocking proper-ties.47 5-Hydroxypropafenone exhibits antiarrhythmicproperties similar to that of propafenone but lack its β-blocking properties.45,48 Therefore antiarrhythmic effi-cacy of propafenone is mediated by both propafenone


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and 5-hydroxypropafenone in extensive metabolizerswhereas in poor metabolizers, propafenone is the activecompound responsible for antiarrhythmic efficacy. Inthis study no β-blocking effects, assessed by the mea-surement of the RR intervals, were noted betweenextensive metabolizers and poor metabolizers afteradministration of propafenone alone. These results arein agreement with those of others who reported noreduction in the maximal heart rate during exercise afterpropafenone administration at doses required to con-trol ventricular arrhythmias.49 However, Lee et al50

clearly established the β-blocking properties ofpropafenone, especially in poor metabolizers.

In conclusion we demonstrated in this study thatpropafenone significantly alters the metabolism of mex-iletine enantiomers caused by an inhibition of CYP2D6activity. Inhibition by propafenone of CYP2D6-depen-dent metabolic pathways of mexiletine was similar tothat observed with quinidine, another potent inhibitorof CYP2D6. This drug interaction could be of clinicalrelevance in 90% of the white population, who areextensive metabolizers of CYP2D6. These results couldbe different in other populations where the phenotyperepartition is different.

Concomitant administration of the two drugs inhealthy volunteers was not associated with significantchanges on electrocardiographic parameters. However,potentiation of drug effects could predispose to proar-rhythmia in patients with underlying cardiac ischemicdisease. Slow-dose titration when the two drugs areused concomitantly may decrease the risk of drug-related side effects because lower doses of the twoagents could be used. Finally, we propose that changesin pharmacokinetics of mexiletine explain, at least inpart, the increased efficacy observed during the combi-nation treatment of mexiletine and propafenone in casesthat do not respond to treatment with single antiar-rhythmic agents.

We thank Esther Pouliot, Sylvie Pilote, Michel Blouin, and VickyFalardeau for technical assistance and Serge Simard for statisticalanalysis.

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Pharmacokinetic and pharmacodynamic interaction between mexiletine and propafenone in human beings*1