Mexiletine Concentrations Research Articles

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.

Evaluation of mexiletine clearance in a Japanese population.

To evaluate mexiletine clearance in a Japanese population and to clarify the roles of CYP2D6 and CYP1A2 in mexiletine disposition. Concentrations of serum and urinary mexiletine and its metabolites were determined and mexiletine clearances were estimated in 334 inpatients receiving mexiletine therapy. Concentrations of mexiletine and its metabolites in serum and urine samples were determined by HPLC. Although interindividual variation of mexiletine clearance was small, the effect of age on mexiletine clearance was comparatively large. Mexiletine clearance in patients with dilated cardiomyopathy (DCM) was decreased when compared with other diagnoses (Non-DCM). The fractional contents of p-hydroxymexiletine (POH) and 2-hydroxymexiletine (OHMEX) in urine amounted to approximately 50%. Almost all of the POH was conjugated, whereas less than one-third of the OHMEX was conjugated. Although no significant differences in POH and OHMEX were observed between patients with DCM and those without, a trend toward an increase in conjugation pathway of DCM patients was observed. The interindividual variation of mexiletine clearance was small, while the effect of age on the mexiletine clearance in Non-DCM was comparatively large. A significant difference in mexiletine clearance between patients with DCM and those with Non-DCM was observed. Therefore, when mexiletine is administered to patients with DCM, careful monitoring is needed.

Mild alkalinization and acidification differentially modify the effects of lidocaine or mexiletine on vasorelaxation mediated by ATP-sensitive K+ channels.

The previous study by the authors showed that the class Ib antiarrhythmic drug lidocaine impairs but mexiletine augments vasorelaxation mediated by adenosine triphosphate-sensitive K+ channels. Lidocaine and mexiletine have different values of the negative logarithm of the drug-proton dissociation constant, indicating that the ion channel-blocking effects of these drugs under different pH levels may vary. However, the role of pH in the effects of lidocaine and mexiletine on vasodilation mediated by K+ channels has not been studied. Therefore, the current study was designed to examine whether the inhibition and augmentation of vasorelaxation in response to an adenosine triphosphate-sensitive K+ channel opener, levcromakalim, by the clinically relevant concentrations of lidocaine or mexiletine are modified by mild alkalinization or acidification in the isolated rat aorta. Rings of the rat aorta without endothelium were suspended for isometric force recording. Three types of modified Krebs-Ringer solutions (pH 7.2, 7.4, and 7.6) were prepared by changing the composition of NaCl and NaHCO3. During contractions in response to phenylephrine (3 x 10(-7) M), relaxations in response to levcromakalim (10(-8) to 10(-5) M) were obtained. Lidocaine (10(-5) to 10(-4) M), mexiletine (10(-5) to 10(-4) M), or glibenclamide (10(-5) M) was applied 15 min before addition of phenylephrine. Relaxations in response to levcromakalim, which are abolished by the selective adenosine triphosphate-sensitive K+ channel antagonist glibenclamide (10(-5) M), were not different among the three pH groups. In the normal Krebs-Ringer solution of pH 7.4, lidocaine significantly reduced these relaxations in a concentration-dependent fashion. Alkalinization of pH 7.6 augmented the inhibitory effect of lidocaine on these relaxations, whereas acidification of pH 7.2 substantially abolished this effect. In contrast, mexiletine pH independently augmented relaxations in response to levcromakalim. Glibenclamide (10(-5) M) abolished these relaxations in arteries treated with mexiletine (10(-4) M) in any pH group. These results suggest that even under conditions of such mild alkalosis or acidosis, vasorelaxation via adenosine triphosphate-sensitive K+ channels is dependent on pH in the presence of clinically relevant concentrations of lidocaine but not mexiletine.

Enantioselective analysis of N-hydroxymexiletine glucuronide in human plasma for pharmacokinetic studies.

Enzymatic hydrolysis with beta-glucuronidase/sulfatase was used for the enantioselective determination of N-hydroxymexiletine glucuronide in plasma for pharmacokinetic studies. N-Hydroxymexiletine glucuronide was determined as the quantity of mexiletine released by hydrolysis (difference between the enantiomeric concentrations of mexiletine obtained with and without hydrolysis). Plasma samples (100 microliters) were treated at pH 5.0 with 10 mg of the enzyme (Limpet Acetone Powder type I) for 16 hr at 37 degrees C and extracted at pH 10.4 with diisopropyl ether. Chiral mexiletine discrimination was obtained by reaction with o-phthalaldehyde/N-acetyl-L-cysteine, separation of the resulting diastereomers on a C-18 reversed-phase column with a mobile phase of methanol-0.05 N acetate buffer, pH 5.5 (6.5:3.5, v/v), and fluorescence detection (lambda ex 350 nm, lambda em 455 nm). The performance characteristics for the enantioselective analysis of mexiletine preceded by enzymatic hydrolysis were recovery approximately 90%, quantification limit 1 ng/ml, and linearity up to 1000 ng/ml plasma for both enantiomers. The coefficients of variation obtained in the study of intra- and inter-day precision were respectively 5% and 7% for both enantiomers. The assay was shown to be suitable for a pharmacokinetic study performed in a patient with the arrhythmic form of chronic Chagas' heart disease treated with 200 mg t.i.d. of racemic mexiletine hydrochloride. The high sensitivity of the method allows analysis of only 100 microliters plasma.

Effects of mexiletine on ATP sensitive K+ channel of rat skeletal muscle fibres: a state dependent mechanism of action.

1. The effects of mexiletine were evaluated on the ATP-sensitive K+ channel (K(ATP)) of rat skeletal muscle fibres using patch clamp techniques. The effects of mexiletine were studied on macropatch currents 20 s (maximally activated), 8 min (early stage of rundown) and 15 min (late stage of rundown) after excision in the absence or in the presence of internal ADP (50-100 microM) or UDP (500 microM). In addition, the effects of mexiletine were tested on single channel. 2. In the absence of ADP and UDP, mexiletine inhibited the current through maximally activated channels with an IC50 of -5.58+/-0.3 M. Nucleoside diphosphates shifted the current versus mexiletine concentration relationship to the right on the log concentration axis. UDP (500 microM) was more efficacious than ADP (50-100 microM) in this effect. 3. At the early stage of rundown, the sensitivity of the channel to mexiletine was reduced and nucleoside diphosphates, particularly UDP, antagonized the effect of mexiletine. At the late stage of rundown, mexiletine did not affect the currents. 4. At the single channel level, 1 microM mexiletine reduced the mean burst duration by 63% and prolonged the arithmetic mean closed time intervals between the bursts of openings without altering the open time and closed time distributions. Mexiletine did not affect the single channel conductance. 5. These results show that in skeletal muscle, mexiletine is a state-dependent K(ATP) channel inhibitor which either acts through the nucleotide binding site or a site allosterically coupled to it.

Effects of local anesthetics on Na+ channels containing the equine hyperkalemic periodic paralysis mutation.

We examined the ability of local anesthetics to correct altered inactivation properties of rat skeletal muscle Na+ channels containing the equine hyperkalemic periodic paralysis (eqHPP) mutation when expressed in Xenopus oocytes. Increased time constants of current decay in eqHPP channels compared with wild-type channels were restored by 1 mM benzocaine but were not altered by lidocaine or mexiletine. Inactivation curves, which were determined by measuring the dependence of the relative peak current amplitude after depolarization to -10 mV on conditioning prepulse voltages, could be shifted in eqHPP channels back toward that observed for wild-type (WT) channels using selected concentrations of benzocaine, lidocaine, and mexiletine. Recovery from inactivation at -80 mV (50-ms conditioning pulse) in eqHPP channels followed a monoexponential time course and was markedly accelerated compared with wild-type channels (tauWT = 10.8 +/- 0.9 ms; taueqHPP = 2.9 +/- 0.4 ms). Benzocaine slowed the time course of recovery (taueqHPP,ben = 9.6 +/- 0.4 ms at 1 mM) in a concentration-dependent manner. In contrast, the recovery from inactivation with lidocaine and mexiletine had a fast component (taufast,lid = 3.2 +/- 0.2 ms; taufast,mex = 3.1 +/- 0.2 ms), which was identical to the recovery in eqHPP channels without drug, and a slow component (tauslow,lid = 1,688 +/- 180 ms; tauslow,mex = 2,323 +/- 328 ms). The time constant of the slow component of the recovery from inactivation was independent of the drug concentration, whereas the fraction of current recovering slowly depended on drug concentrations and conditioning pulse durations. Our results show that local anesthetics are generally incapable of fully restoring normal WT behavior in inactivation-deficient eqHPP channels.

Gas chromatography-electron ionization and chemical ionization mass spectrometric analysis of serum mexiletine concentration after derivatization with 2,2,2-trichloroethyl chloroformate: a novel derivative.

Mexiletine (Mexitil) is an antiarrhythmic agent used in the treatment of ventricular arrhythmia. The drug has a narrow therapeutic window, and monitoring its serum concentration is recommended. The authors describe a gas chromatography-mass spectrometric (GC/MS) assay of mexiletine using selected ion monitoring. Mexiletine was extracted from alkaline serum with dichloromethane followed by derivatization with 2,2,2-trichloroethyl chloroformate. The reaction was completed in 30 minutes at 70 degrees C. N-propylamphetamine was used as the internal standard. The ions monitored were m/z 58, 102, 122, 232, and 234 for derivatized mexiletine and m/z 56, 91, 131, 260, and 262 for the derivatized internal standard. The within-run precision at a serum mexiletine concentration of 1 mg/l was 1.7% (mean = 0.981, SD = 0.017 mg/l, n = 8) and the between-run precision was 3.3% (mean = 0.983, SD = 0.033 mg/l, n = 6). The assay was linear for serum mexiletine concentrations of 0.2 to 2.5 mg/l. The detection limit was 0.1 mg/l. The authors observed no carry-over problem in their assay. They observed a good correlation between mexiletine concentrations measured by a reference laboratory (Associated Regional University Pathologists, Salt Lake City, UT, U.S.A.) and by the new GC/MS assay.

Effects of lidocaine and mexiletine on defibrillation energy requirements in animals treated with flecainide

We previously reported that mexiletine alone did not increase the ventricular defibrillation threshold (DFT). However it has been stressed that the interaction of antiarrythmic drugs may be one of the cause of sudden death in patients taking flecainide or encainide. In the present study, the effect of lidocaine and mexiletine combined with flecainide on DFT was investigated. Experiments were performed on 27 mongrel dogs. Flecainide 2 mg kg −1 was administered i.v. as a loading dose and repeated for maintenance. Lidocaine ( n=10) or mexiletine ( n=10), was cumulatively administered 15 min later. Saline was administered in control group ( n=7). In these groups, fibrillation/defibrillation trials were repeated. The flecainide concentration ranged from 0.84 to 1.02 μg ml −1. The lidocaine and mexiletine concentrations increased up to 12.54 and 7.47 μg ml −1, respectively. DFT 15, 15 min after the administration of flecainide, increased from 2.0 to 3.2 J in lidocaine group (mean±S.E.M.; P<0.05), from 2.1 to 3.7 J in mexiletine group (mean±S.E.M.; P<0.05). DFT increased with lidocaine concentrations of 3.42 μg ml −1 or higher, and mexiletine of 3.60 μg ml −1 or higher ( P<0.05). In conclusion, both lidocaine and mexiletine elevated the DFT in the dog treated with flecainide, especially with lidocaine in a therapeutic concentration.

Gas chromatographic–mass spectrometric determination of serum mexiletine concentration after derivatization with perfluorooctanoyl chloride, a new derivative

Mexiletine is an antiarrhythmic agent used in the treatment of ventricular arrhythmia. The drug has a narrow therapeutic window which necessitates monitoring its serum concentrations. We describe a gas chromatographic–mass spectrometric analysis of mexiletine using selected ion monitoring. Mexiletine was extracted from alkaline serum with dichloromethane and then derivatized with perfluorooctanoyl chloride. The derivatization reaction was completed in 20 min at 80°C. We used N-propylamphetamine as the internal standard. The ions monitored were m/ z 122, 454 and 575 for the derivatized mexiletine and m/ z 91, 118, 440 and 452 for the derivatized internal standard. The within-run precision at a serum mexiletine concentration of 1 mg/l was 1.9% (mean=0.98, S.D.=0.019 mg/l, n=7) and the between-run precision was 2.5% (mean=0.99, S.D.=0.025 mg/l, n=7). The assay was linear for serum mexiletine concentrations of 0.2 to 4 mg/l. The detection limit was 0.1 mg/l. The average recoveries of mexiletine and the internal standard were 80% and 84%, respectively at a mexiletine concentration of 1 mg/l. There was no carry over problem in our assay. We observed a good correlation between mexiletine concentrations measured by a reference laboratory (GC) and by our new GC–MS assay.

Lack of pharmacokinetic interaction between mexiletine and omeprazole.

To investigate the effect of omeprazole on the pharmacokinetics of mexiletine. Nine healthy male Japanese volunteers participated in a crossover study. On day 1, the subjects received mexiletine 200 mg. On days 2-7, they received omeprazole 40 mg, and on day 8 they received mexiletine 200 mg and omeprazole 40 mg concomitantly. Serum concentrations of mexiletine were determined just before drug administration and at 1, 2, 3, 4, 6, 8, 12, and 24 hours on day 1 and day 8. No differences in mexiletine concentrations were observed between the two phases of the study. The mean AUCs after administration of mexiletine alone and in combination with omeprazole 40 mg/d were 6.26 and 6.20 ng.h/L, respectively. These findings suggest that omeprazole does not affect mexiletine metabolism.

Effects of Sodium Channel Block with Mexiletine to Reverse Action Potential Prolongation in In Vitro Models of the Long QT Syndrome

Recent clinical studies have reported a greater effectiveness of sodium channel block with mexiletine to abbreviate the QT interval in patients with the chromosome 3 variant (SCN5A, LQT3) of the long QT syndrome (LQTS) than those with the chromosome 7 form of the disease (HERG, LQT2), suggesting the possibility of gene-specific therapy for the two distinct forms of the congenital LQTS. Experimental studies using the arterially perfused left ventricular wedge preparation have confirmed these clinical observations on the QT interval but have gone on to further demonstrate a potent effect of mexiletine to reduce dispersion of repolarization and prevent torsades de pointes (TdP) in both LQT2 and LQT3 models. A differential action of sodium channel block on the three ventricular cell types is thought to mediate these actions of mexiletine. This study provides a test of this hypothesis by examining the effects of mexiletine in isolated canine ventricular epicardial, endocardial, and M region tissues under conditions that mimic the SCN5A and HERG gene defects. We used standard microelectrode techniques to record transmembrane activity from endocardial, epicardial, mid-myocardial, and transmural strips isolated from the canine left ventricle. d-Sotalol, an IKr blocker, was used to mimic the HERG defect (LQT2), and ATX-II, which increases late Na channel current, was used to mimic the SCN5A defect (LQT3). d-Sotalol (100 microM) preferentially prolonged the action potential of the mid-myocardial M cell (APD90 increased from 340 +/- 65 to 623 +/- 203 msec) as did ATX-II (10 to 20 nM; APD90 increased from 325 +/- 51 to 580 +/- 178 msec; basic cycle length = 2000 msec), thus causing a marked increase in transmural dispersion of repolarization (TDR). Mexiletine (2 to 20 microM) dose-dependently reversed the ATX-II-induced prolongation of APD90 in all three cell types. Mexiletine also reversed the d-sotalol-induced prolongation of the M cell action potential duration (APD), but had little effect on the action potential of epicardium and endocardium. Due to its preferential effect to abbreviate the action potential of M cells, mexiletine reduced the dispersion of repolarization in both models. Low concentrations of mexiletine (5 to 10 microM) totally suppressed early afterdepolarization (EAD) and EAD-induced triggered activity in both models. Our results indicate that the actions of mexiletine are both cell and model specific, but that sodium channel block with mexiletine is effective in reducing transmural differences in APD and in abolishing triggered activity induced by d-sotalol and ATX-II. The data suggest that mexiletine's actions to reduce TDR and prevent the induction of spontaneous and programmed stimulation-induced TdP in these models are due to a preferential effect of the drug to abbreviate the APD of the M cell and to suppress the development of EADs. The data provide further support for the hypothesis that block of the late sodium current may be of value in the treatment of LQT2 as well as LQT3 and perhaps other congenital and acquired (drug-induced) forms of LQTS.

Sodium channel block with mexiletine is effective in reducing dispersion of repolarization and preventing torsade des pointes in LQT2 and LQT3 models of the long-QT syndrome.

This study examines the contribution of transmural heterogeneity of transmembrane activity to phenotypic T-wave patterns and the effects of pacing and of sodium channel block under conditions mimicking HERG and SCN5A defects linked to the congenital long-QT syndrome (LQTS). A transmural ECG and transmembrane action potentials from epicardial, M, and endocardial or Purkinje cells were simultaneously recorded in an arterially perfused wedge of canine left ventricle. d-Sotalol was used to mimic LQT2, whereas ATX-II mimicked LQT3. d-Sotalol caused a preferential prolongation of the M cell action potential duration (APD90, 291+/-14 to 354+/-35 ms), giving rise to broad and sometimes low-amplitude bifurcated T waves and an increased transmural dispersion of repolarization (TDR, 51+/-15 to 72+/-17 ms). QT interval increased from 320+/-13 to 385+/-37 ms. ATX-II produced a preferential prolongation of the M cell APD90 (280+/-25 to 609+/-49 ms) and caused a marked delay in the onset of the T wave and a sharp rise in TDR (40+/-5 to 168+/-40 ms). QT-, APD90-, and dispersion-rate relations were much steeper in the ATX-II than in the d-sotalol model. Mexiletine (2 to 20 micromol/L) dose-dependently abbreviated the QT interval and APD90 of all cell types, more in the ATX-II than in the d-sotalol model, but decreased TDR equally in the two models. Mexiletine 2 to 5 micromol/L totally suppressed spontaneous torsade de pointes (TdP) and reduced the vulnerable window during which single extrastimuli could induce TdP in both models. Higher concentrations of mexiletine (10 to 20 micromol/L) totally suppressed stimulation-induced TdP. Our results suggest that although pacing and sodium channel block are very effective in abbreviating the QT interval and TDR in LQT3, these therapeutic approaches may also be valuable in reducing the incidence of arrhythmogenesis in LQT2.

Correlation between electrophysiological effects of mexiletine and ischemic protection in central nervous system white matter.

Protection of CNS white matter tracts in brain and spinal cord is essential for maximizing clinical recovery from disorders such as stroke or spinal cord injury. Central myelinated axons are damaged by anoxia/ischemia in a Ca(2+)-dependent manner. Leakage of Na+ into the axoplasm through Na+ channels causes Ca2+ overload mainly by reverse Na(+)-Ca2+ exchange. Na+ channel blockers have thus been shown to be protective in an in vitro anoxic rat optic nerve model. Mexiletine (10 microM-1 mM), an antiarrhythmic and use-dependent Na+ channel blocker, was also significantly protective, as measured by recovery of the compound action potential after a 60 min anoxic exposure in vitro. More importantly, mexiletine (80 mg/kg, i.p.) also significantly protected optic nerves from injury in a model of in situ ischemia. This in situ model is more clinically relevant as it addresses drug pharmacokinetics, toxicity and CNS penetration. Optic nerve recovery cycles (defined as shifts in latency of compound action potentials with paired stimulation) were used to measure the concentration of mexiletine in optic nerves after systemic administration, estimated at approximately 42 microM 1 h after a single dose of 80 mg/kg, i.p. These results indicate that mexiletine is able to penetrate into the CNS at concentrations sufficient to confer significant protection. Na+ channel blockers such as mexiletine may prove to be effective clinical therapeutic agents for protecting CNS white matter tracts against anoxic/ischemic injury.

Mexiletine has no effect on defibrillation energy requirements in dogs.

Many of the antiarrhythmic drugs produce a rise in the ventricular defibrillation threshold (DFT). Although mexiletine has also been reported as the probable cause of a significant elevation of DFT, there has been no previous study; therefore, the effect of mexiletine on DFT was investigated in the present study. The experiments were performed on ten mongrel dogs in the open-chest state using general anesthesia. Mexiletine 1, 2, 4, 6, or 8 mg/kg was administered as the loading dose, followed by the same dose/kg per hour. In these five groups, fibrillation/defibrillation (F/D) trials were performed repeatedly every 10 minutes, until 60 minutes after starting the maintenance dose. F/D trials were also performed at 30, 45, and 60 minutes after the completion of mexiletine infusion. The heart was allowed to fibrillate for a total of 30 seconds. Applying internal paddles to the heart, energies of 2, 3, 5, 7, 10, 20, and 30 J maximum were used. The minimal energy shock that caused defibrillation was defined as the DFT. The mexiletine concentration in each group changed from 0 to 6.11 micrograms/mL, DFT ranged from 2-10 J, and no statistical correlation was found between mexiletine concentration and DFT. We conclude that mexiletine does not induce an increase in DFT in dogs.

Salivary Excretion of Mexiletine after Bolus Intravenous Administration in Analbuminemic Rats.

To clarify the effect of plasma albumin on the salivary excretion of mexiletine, we have investigated the kinetics of and correlation between plasma and saliva levels following bolus intravenous administration (5 mg/kg) in male Sprague-Dawley rats (analbuminemic and normal). Parotid and mandibular saliva was collected separately by stimulating salivation with constant rate infusion of pilocarpine (50 μg/kg/min). In both rats, the mexiletine levels in plasma, parotid and mandibular saliva declined biexponentially with time in almost parallel fashion. Although the mexiletine levels in both types of saliva were lower than that in plasma (p < 0.05 or 0.01), the drug level in parotid saliva was always higher than that in mandibular saliva in both groups (p < 0.05 or 0.01). Furthermore, in both rats, significant correlations were observed when all data relating mexiletine concentration in plasma and saliva were included (p < 0.001). The saliva to plasma drug concentration ratios (S/P ratios) for both saliva in analbuminemic rats (0.814±0.162 for parotid saliva, 0.367±0.074 for mandibular saliva) were higher than those in normal rats (0.727±0.110 for parotid saliva, 0.197±0.061 for mandibular saliva) (p < 0.01). These changes in the S/P ratios between both groups could not be explained by the pH for either parotid or mandibular saliva. In contrast, the slight increase in the unbound fraction of the drug in analbuminemic rats, though it was not significant from the unbound fraction in normal rats, tended to be consistent with the difference in the S/P ratios for both salivary glands. These aspects suggest the possibility that the extent of salivary excretion of mexiletine may be influenced by the albumin concentration and dependent on the unbound fraction in plasma.

Effects of hyperkalaemia on the depression of maximum rate of depolarization by class I antiarrhythmic agents in guinea‐pig myocardium

1 Standard microelectrode methods were used to record intracellular action potentials from strips of guinea-pig right ventricular myocardium superfused with either standard physiological saline ([K+] = 5.6 mM) or the same solution modified to contain [K+] = 11.2 mM. 2 The effects on action potential parameters of three therapeutic concentrations of mexiletine, quinidine and disopyramide were studied under both conditions at four different drive rates (interstimulus intervals = 2400, 1200, 600 and 300 ms). 3 Hyperkalaemia in the absence of drugs produced reductions in resting potential (-86.7 +/- 2.5 mV to -71.8 +/- 3.7 mV; n = 30; P < 0.001), maximum rate of depolarization (300 +/- 46.5 V s-1 to 205.6 +/- 37.6 V s-1; P < 0.0001), and action potential duration (205 +/- 26 ms to 188 +/- 32 ms; P < 0.05). 4 All three drugs produced increased depression of maximum rate of depolarization in hyperkalaemia compared to control conditions, but at all three concentrations this enhancement of effect was greater for mexiletine than for quinidine, with disopyramide exhibiting intermediate behaviour. 5 Mexiletine behaved very similarly to therapeutic concentrations of lignocaine as described in previous reports from this laboratory. 6 Quinidine behaved very similarly to Class Ic agents. 7 It is concluded that mexiletine demonstrated significantly greater selectivity for depolarized myocardium than quinidine and that this may have implications in terms of proarrhythmic potential. 8 Disopyramide exhibited intermediate selectivity for depolarized myocardium between mexiletine and quinidine.

Combined class I antiarrhythmic agents have differential effects on tonic and use dependent block of maximum rate of depolarisation of action potentials in guinea pig cardiac muscle.

The aim was to study the difference between tonic and use dependent block of the cardiac sodium channel produced by the combined application of the same subclass of antiarrhythmic agents (class Ia or Ib). Conventional glass microelectrode technique was used to record the maximum rate of depolarisation (dV/dtmax) of action potentials reflecting sodium channel availability, before and after the combined application of quinidine plus disopyramide, aprindine plus lignocaine, aprindine plus mexiletine, and lignocaine plus mexiletine. Guinea pig papillary muscles (n = 4-8 per experiment) were used for the study. All combinations increased tonic block additively compared to use of a single drug. On the other hand, use dependent block was increased by the combination of quinidine 10 microM plus disopyramide 30 microM compared to a single drug, and was not changed by lignocaine 50 microM plus mexiletine 20 microM, whereas it was decreased by aprindine 3 microM plus lignocaine 50 microM or mexiletine 20 microM. When concentrations of mexiletine and lignocaine were increased, both tonic and use dependent block in a single drug were increased dose dependently, whereas the combination produced an additive increase in tonic block but no change in use dependent block compared to a single drug. The results suggested that the binding and unbinding process of the drug to produce tonic block was different from that to produce use dependent block, and that combination of different drugs produced diverse effects on use dependent block even though state dependent affinity of individual drugs seemed similar. These two factors must be born in mind in evaluating the combination therapy.

A sensitive determination method for mexiletine derivatized with dansyl chloride in rat plasma utilizing a HPLC peroxyoxalate chemiluminescence detection system.

A sensitive determination method for a non-fluorescent anti-arrhythmic drug, mexiletine, in rat plasma is presented utilizing a HPLC peroxyoxalate chemiluminescence (PO-CL) detection system. After an internal standard (4-methylmexiletine, 4.35 pmol) and 0.1 N sodium hydroxide solution were added to 5 microL rat plasma, the solution was poured onto an Extrelut 1 column. Both mexiletine and the internal standard were eluted with diethy ether and then the eluate was evaporated to dryness. The residue was dissolved in 0.2 M borate buffer (pH 8.5) and mixed with dansyl chloride (75 nmol) in acetronitrile. After standing of 90 min at room temperature, 0.5 N HCl was added to the reaction mixture to stop the reaction and a 2/45 aliquot of the mixture was subjected to a HPLC PO-CL detection system using bis(4-nitro-2(3,6,9-trioxadecyloxycarbonyl)phenyl) oxalate (TDPO) and hydrogen peroxide. The calibration curve for mexiletine in rat plasma was linear over the range 20-100 ng/mL plasma (20.6-103 fmol/injection). The detection limit (S/N = 2) was 1.0 fmol over the whole procedure. The method was applied to the measurement of the time courses of plasma mexiletine concentration after oral administration of the drug [25 mg (115.9 mumol)/kg] to rats.

高速液体クロマトグラフィーによるメキシレチンの血清中濃度測定およびその蛋白結合率

A new method to determine serum mexiletine (MX) concentrations using high-performance liquid chromatography (HPLC) was established.This method could reduce a sample volume to 100μ1 of serum and could shorten the pretreatment time to less than 10 minutes by using Chem Elut minicolumn. The results obtained by this method (n=28) correlated well with those obtained by gas chromatography method (r=0.997).Moreover, this method had a good recovery and reproducibility, suggesting that it is an excellent method for determining serum MX concentrations.Using this HPLC method, serum protein binding of MX was studied in healthy subjects and patients with chronic renal failure (CRF). The protein binding of MX was 60.83±4.37% in healthy subjects (n=6) and 52.45±6.22% in CRF (n=9).The protein binding of MX in CRF was significantly decreased, compared with healthy subjects, indicating an apparent elevation of free drug concentrations.In general, dose adjustment of MX in CRF is considered to be unnecessary. However, free drug concentrations may participate in the appearance of effects and adverse reactions. The possibility of enhanced pharmacological effects and increased adverse reactions due to such variations of protein binding in CRF should be also considered.

Cardiodepressant effects of mexiletine in patients with severe left ventricular dysfunction.

Mexiletine is thought to exert minimal negative inotropic actions, but its effects have not been evaluated in patients with severe congestive heart failure. The haemodynamic response to an oral loading dose of mexiletine (400 mg) was assessed in 20 patients with severe chronic heart failure. Mexiletine caused marked haemodynamic deterioration, with stroke work index decreasing in 18 of the patients. Two hours after mexiletine, mean cardiac and stroke work indexes decreased by 15% and 25%, respectively (both P less than 0.001), while heart rate and systemic vascular resistance increased by 10% and 20%, respectively (both P less than 0.05). Simultaneously, left ventricular filling pressure and right atrial pressure increased by 37% and 36%, respectively (both P less than 0.001), but mean arterial pressure did not change. Furthermore, clinical deterioration, with onset of dyspnoea at rest, developed in five patients at the time of peak haemodynamic effect. Plasma mexiletine concentrations were within the accepted therapeutic range of 0.5 to 2.0 micrograms.ml-1 in all but two of the patients. Nevertheless, the plasma concentration was an important determinant of haemodynamic effect. The stroke work index decreased by 38% in the patients with a mexiletine level above the median value of 1.3 micrograms.ml-1 (range 25 to 56%), but only 13% (range 15 to 43) in patients with lower plasma concentrations. In conclusion, although mexiletine may cause cardiodepressant effects in any patient with severe left ventricular dysfunction, dosing which results in a high (but still therapeutic) plasma level is more likely to cause haemodynamic deterioration.