Human moricizine metabolism. II. Quantification and pharmacokinetics of plasma and urinary metabolites.

1. The metabolism of moricizine.HCl was studied in 12 male volunteers dosed with 250 mg (300 microCi) 14C-radiolabelled drug. 2. Moricizine was biotransformed to many metabolites in humans (at least 35 plasma and 51 urine metabolites). 3. Urine and faecal combined mean (range) recovery accounted for 90.2% (73.4-101.6%) of the administered radioactivity, with most of the recovered radioactivity present in faeces (mean 58.4%; range 45.6-64.7%). Mean (range) urinary recovery was 31.8% (26.2-36.9%), with <1% of the dose recovered as intact moricizine, and no one metabolite accounting for >2.5% of the dose. 4. Total radioactivity (TR) plasma t1/2 was 85.2 h, while that for moricizine was 2.4 h. Mean half-lives for plasma metabolites ranged from 2.9 to 23.6 h. The largest portion (11%) of TR AUC (area under the plasma concentration-time curve) was attributed to 2amino-10-glucuronophenothiazine. Each of the other metabolites accounted for less of the TR AUC than parent drug except for two unidentified peaks which had comparable areas (approximately 5% of the total radioactivity area). 5. Two identified moricizine metabolites, 2-amino-10-(3-morpholinopropionyl) phenothiazine and ethyl [10-(3-aminopropionyl) phenothiazin-2-yl] carbamate, possess the structural characteristics proposed for class 1 anti-arrhythmic activity (pendant amine functionality) and have plasma half-lives 4-7-fold longer than moricizine.

Moricizine bioavailability via simultaneous, dual, stable isotope administration: bioequivalence implications.

The relative bioavailability of a 200 mg film-coated tablet of [12C]moricizine.HCl in comparison to a 200 mg [13C6]moricizine.HCl oral solution was determined after simultaneous administration to 8 young healthy male subjects. Concentrations of [12C]moricizine.HCl and [13C6]moricizine.HCl were determined by thermospray liquid chromatography-mass spectrometry (LC-MS) using [2H11]moricizine.HCl as the internal standard. The mean absorption and disposition parameters of the tablet versus the solution were the following (%CV): maximum concentration, 0.83 (39%) versus 0.79 (39%) microgram/mL; time of maximum concentration, 0.81 (40%) versus 0.65 (28%) hours; area under the concentration-time curve (AUC), 1.58 (39%) versus 1.49 (37%) micrograms.h/mL; apparent oral clearance, 150.7 (52%) versus 158.1 (50%) L/h; and t1/2, 1.9 (42%) versus 1.9 (42%) hours. The AUC for the tablet averaged 106% of the solution, which likely reflects a greater first-pass effect with the oral solution. Partitioning sources of variation confirmed the low (< 6%) intrasubject coefficient of variation (cv epsilon) afforded via the single-period, dual-isotope design. In contrast, a previous study using the conventional two-period crossover design determined the cv epsilon about moricizine metrics to be in excess of 30%, resulting in classification of this drug as having highly variable absorption. The results of this study further illustrate the benefits of dual, stable isotopes to assess bioavailability and bioequivalence. This paradigm results in a reduction in experimental time and subject inconvenience and lower costs in comparison with the standard crossover study. Perhaps most important is the improved statistical power for the evaluation of bioavailability or bioequivalence in the absence of period and sequence effects that confound the assessment of intrasubject variation in the standard crossover design.

[The pharmacology of the new combined anti-arrhythmia preparation metatsizin]. / K farmakologii novogo kombinirovannogo antiaritmicheskogo preparata metatsizina.

The combined antiarrhythmic effect of ethmosin and ethacisin in various dose ratios was studied in conscious dogs with two-stage ligation of the coronary artery (after Harris). A 6:1 ratio was found to be optimal for manifestation of the antiarrhythmic effect. In such a ratio of the doses the antiarrhythmic effect of a combination of ethmosin and ethacisin is essentially higher than the activity of each component. On the grounds of these data a combined antiarrhythmic drug methacisin was developed. It possesses a broad spectrum of antiarrhythmic activity. The drug is effective on models of arrhythmias specific of class I, III, and IV antiarrhythmics. Metacisin does not change hemodynamics and activity of the heart. Study of metacisin pharmacokinetics showed that it possesses bioavailability twice that of ethmosin tablets taken separately and four times that of ethasicin.

Pharmacokinetic interactions of moricizine and diltiazem in healthy volunteers.

Sixteen healthy male volunteers completed a nonrandomized, sequential, three-phase study. The three phases were 1) moricizine at 250 mg every 8 hours for 7 days with 12 days washout; 2) diltiazem at 60 mg every 8 hours for 7 days; and 3) concomitant administration of moricizine at 250 mg and diltiazem at 60 mg every 8 hours for 7 days. The plasma concentration-time profiles were obtained at the end of each phase for moricizine, diltiazem (with its metabolites desacetyl-diltiazem and N-desmethyl-diltiazem), and both when administered together. Under steady-state conditions, there was a two-way (opposing) pharmacokinetic drug interaction when moricizine and diltiazem were coadministered in healthy volunteers. Both maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to the end of administration (AUC tau) of moricizine increased significantly by 88.9% and 121.1%, respectively. Oral clearance (Clo) decreased by 54%. The terminal half-life (t1/2) of moricizine was not affected, however (2.1 +/- 0.5 hours versus 2.4 +/- 0.7 hours). It is believed that these changes were due to the inhibition of hepatic metabolism by diltiazem, which resulted in an increased systemic availability of moricizine. Moricizine had opposite effects on the pharmacokinetics of diltiazem. Moricizine decreased the Cmax of diltiazem significantly (by 36%) and increased Clo by 52%. A small but statistically significant decrease in the t1/2 from 4.6 +/- 1.3 hours to 3.6 +/- 0.7 hours was observed. Despite this result, no remarkable changes (e.g., in Cmax, AUC, or t1/2) were found for the two major diltiazem metabolites desacetyl-diltiazem and N-desmethyl-diltiazem. It appears that the pharmacokinetic interaction of moricizine and diltiazem was metabolic. With the increase in moricizine concentrations and the decrease in diltiazem concentrations, adjustments in dose may be required to achieve optimal therapeutic response when coadministering both agents.

[Studies on ethmozine sustained-release tablet remaining-floating in stomach].

An oral sustained-release system of ethmozine (E-HBS) was developed. The in vitro release characteristics of E-HBS were shown primarily to be of the first order of kinetics (Kr = 0.2436 h-1). The gamma-scintiphotographic study showed that E-HBS remained in the human stomach for more than 6 hours after ingestion, much longer than the conventional tablet (1-1.5 h). The plasma concentration-time curve of E-HBS exhibited typical sustained-release characteristics. The percentage of drug released in vitro vs the percentage of drug release in vivo of E-HBS indicated excellent linearity.

Pharmacokinetics of moricizine in young patients.

Moricizine is a novel phenothiazine antiarrhythmic agent that depresses the activity of ectopic foci, has a low incidence of adverse effects relative to other agents, and is useful in treating pediatric atrial ectopic tachycardia. A study was conducted to determine the pharmacokinetics of moricizine in children after oral administration. Moricizine was isolated from frozen serum obtained from four male patients (ages 7, 8, 9, and 18 years) receiving the drug for supraventricular tachycardia and analyzed by high-performance liquid chromatography with ultraviolet detection according to an established protocol. Peak serum levels were between 400 and 2000 ng/mL. Elimination of moricizine did not follow simple single-compartment pharmacokinetics. In three patients we observed an increase or slower decline in blood level occurring after 4 hours. Because of the paroxysmal nature of the tachycardias, decreases in patient heart rate could not be correlated with moricizine blood level. These results suggest that the pediatric pharmacokinetics of moricizine excretion are complex and may differ from those seen in adults.

Isolation and characterization of sulphoxidation metabolites of moricizine in rat and human biological fluids.

The sulphoxidation metabolites of moricizine, moricizine sulphoxide (M-sulphoxide) and moricizine sulphone (M-sulphone) were isolated and identified in the rat bile and urine and in human plasma and urine following administration of moricizine hydrochloride. The sulphoxide and sulphone were synthesized chemically by peroxidation of moricizine hydrochloride with hydrogen peroxide at 25 degree C and 60 degree C, respectively, and were characterized by melting point determination (MP), infrared spectroscopy (IR), mass spectroscopy (MS), thin layer chromatography (TLC) and high performance liquid chromatography (HPLC). In the rats (n=7), which were kept in metabolic cages and given intravenous moricizine (0.72 mg), the mean +/- SD percentages recovered in the urine as moricizine, M-sulphoxide and M-sulphone were 0.11 +/- 0.09%, 0.74 +/- 0.45% and 5.16 +/- 4.24%, respectively. The corresponding recoveries in the bile were 0.13 +/- 0.04% as moricizine, 3.39 +/- 1.62% as M-sulphoxide and 2.16 +/- 1.07% as M-sulphone. After an oral dose of moricizine HCl (300 mg) the plasma concentrations of moricizine, M-sulphoxide and M-sulphone at 4 h in two healthy subjects were 0.43, 0.11 and 0.10 microg/ml and 0.32, 0.17 and 0.27 microg/ml, respectively for Subject 1 and Subject 2. The percentages of dose recovered in the urine as moricizine, M-sulphoxide and M-sulphone were 0.14 and 0.02%, 0.27 and 0.36%, and 0.30 and 0.24%, respectively for Subject 1 and Subject 2. It is suggested that an investigation of the disposition of moricizine and its sulphoxidation metabolites in patients will be valuable for elucidating the prolonged effects in the treatment of ventricular arrhythmias.

Moricizine concentration to guide arrhythmia treatment: with attention to elderly patients.

To test the relationship between plasma moricizine concentration and the electrocardiogram (ECG) and arrhythmia suppression, 17 symptomatic cardiac patients with 30 or more ventricular premature complexes per hour were studied. Seven patients were mature adults, less than 60 years of age; and ten were elderly adults, more than 60 years of age. During steady-state moricizine therapy, patients had plasma moricizine concentration determined over a dosing interval, and had standard 12-lead ECG and a 24-hour ambulatory ECG recorded. The mean moricizine dose was 215 +/- 29 mg every 8 hours; mean maximal moricizine concentration was 1.4 +/- 0.84 micrograms/ml; and mean t1/2 beta was 1.5 +/- 0.7 hours. Baseline age-related differences were found, including prolonged electrocardiographic intervals (PR and QRS) (P < .05), increased ventricular arrhythmias (P < .05), and reduction in creatinine clearance (P < .05) in the elderly. Compared with pretreatment values, PR (P < .05) and QRS (P < .05) prolongation was observed, and was more marked in elderly patients. Over a dosing interval, there were dynamic changes on the ECG that paralleled plasma moricizine concentration; that is, peak and nadir intact moricizine concentration occurred simultaneously with ECG changes: QRS and JTc prolonged (P < .05), and PR prolongation approached significance (P = 0.09). Suppression of ventricular premature complexes of 80% or more occurred in 15 patients, and ventricular tachycardia was abolished in 10 of 12 patients. Probit analysis revealed that the therapeutic antiarrhythmic concentration ranged from 0.20 to 3.6 micrograms/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of hepatic disease on the disposition of moricizine in humans.

The pharmacokinetics of moricizine and two of its metabolites, moricizine sulfoxide and phenothiazine-2-carbamic acid ethyl ester sulfoxide, were studied in healthy control subjects and in patients with chronic liver disease (cirrhosis). Moricizine disposition was significantly altered by hepatic cirrhosis. Compared to healthy subjects, the hepatic disease patients had an increased Cmax (59%), an increased t1/2 (141%), and a reduced plasma clearance (71%). Additionally, small but statistically significant increases were observed for tmax and the fraction of moricizine not bound to plasma proteins in patients with hepatic disease. The elimination of both moricizine metabolites was also altered by hepatic dysfunction as indicated by significantly prolonged terminal half-lives. Furthermore, there was a reduction in the conversion of moricizine to moricizine sulfoxide. Both hepatic blood flow and hepatic metabolizing capacity were assessed in all subjects and patients by administration of indocyanine green and antipyrine, respectively. Indocyanine green and antipyrine plasma clearances were decreased by 38 and 51%, respectively, indicating that both functions were diminished by hepatic cirrhosis. We conclude that the moricizine dose required for arrhythmia patients with hepatic disease should be lower, and perhaps, the dosing frequency should be less than in patients with normal liver function.

Enzyme induction by moricizine: time course and extent in healthy subjects.

Moricizine.HCl, a novel phenothiazine derivative with oral antiarrhythmic activity, was examined for its potential to induce its own hepatic metabolism and to alter the pharmacokinetics of the test substrate, antipyrine, in 12 healthy male subjects. Antipyrine oral clearance increased from a starting value of .74 mL/minute/kg to .98 (+32%, P < .01) after 7 days of moricizine administration (250 mg every 8 hours) and to 1.15 mL/minute/kg after 14 days (+47%, P < .05); t1/2 was correspondingly reduced. Moricizine oral clearance increased from a baseline of 3.01 L/hour/kg to 3.62 (+20%, P < .05) after 6 days of oral moricizine and 4.66 (+51%, not significant) after 13 days. Moricizine t1/2 was marginally, but consistently, increased (+23%, P < .05) instead of decreased as one would expect because of enzyme induction, presumably due to a decrease in systemic bioavailability and its influence on the oral volume of distribution. In half of the subjects who discontinued moricizine after 7 days, antipyrine pharmacokinetic values returned to near baseline 7 days later. Although moricizine was able to induce its own hepatic metabolism and that of antipyrine after 6 or 7 days of continuous administration, the electrocardiographic properties of moricizine did not appear to be altered by continuous dosing.

[Determination of ethmozine in human plasma by high performance liquid chromatography and its pharmacokinetics].

Following detailed study, a rapid and sensitive assay for ethmozine in human plasma has been developed using reversed phase high performance liquid chromatography (HPLC). Plasma samples were prepared for analysis by addition of internal standard (5-chloro-2-amino-benzophenone) followed by protein precipitation using acetonitrile. Analytical column was a C18 Spherisorb. The mobile phase consisted of mathanol-water-triethylamine (70:30:0.4, v/v/v, pH 6.5). The column effluent was monitored at 268 nm. The calibration curve was linear in the range from 20 ng/ml to 4000 ng/ml with r = 0.9994. The detection limit of this method was 3 ng/ml. The method showed good precision and the analytical recovery of ethmozine from plasma was 90-105%. The relative standard deviations for within-day and between-day were 2.4-6.3% and 4.5-10.2% respectively. The plasma drug concentration-time course in man after oral administration of 400 mg after conformed to a 1-compartment open model with a first order absorption phase. Mean T1/2 value was 1.75 +/- 0.45 h.

[Pharmacokinetics of moracizine and moracizine sulfoxide in healthy volunteers].

The pharmacokinetics of moracizine (Mor) and moracizine sulfoxide (Mor-SO) determined by reversed phase HPLC was reported. The data in 6 volunteers after a single oral dose (600 mg) showed an one-compartment open model. The peak concentration in plasma (2.1 +/- 0.4 micrograms.ml-1) of Mor reached within 1-2 h. The Mor-SO concentration in plasma was much lower (0.19 +/- 0.06 micrograms.ml-1) than that of Mor, but its elimination T1/2 (2.3 +/- 1.0 h) was similar to that of Mor (1.5 +/- 1.0 h). The recoveries of Mor, Mor-SO, moracizine sulfone (Mor-SO2) in urine within 48 h were 0.07%, 0.25%, and 0.06% of the total dose, respectively. The Mor and Mor-SO concentration ranges in plasma for 9 arrhythmic patients after 2-wk therapeutic trial were 0.09 +/- 0.07 to 0.9 +/- 0.5 microgram.ml-1 and 0.040 +/- 0.023 to 0.15 +/- 0.06 micrograms.ml-1, respectively. These results suggested that cumulative doses would not result in accumulation of the drug and the anti-arrhythmic effect of Mor-SO might not be realized.

Effects of multiple doses of moricizine hydrochloride on its pharmacokinetics and hepatic microsomal enzymes in rats.

We studied the influence of chronic moricizine hydrochloride (MRZ) treatment on the drug's pharmacokinetics and on drug metabolizing enzyme activities in rats. Separate groups of 8 rats (4 males and 4 females) were treated with 40 and 100 mg/kg oral MRZ once daily for 7 days and saline control for 7 days prior to the preparation of hepatic microsomal enzyme suspensions. Depending on the substrate, treatments with multiple oral MRZ increased or decreased hepatic microsomal enzyme activities. For the pharmacokinetic study, rats (4 males and 4 females) were treated with 40 mg/kg oral MRZ once daily for 7 days. A comparison of MRZ pharmacokinetics obtained on day 1 relative to day 7 revealed that both AUC0-t and AUC0-infinity increased about 7-fold in males and 2-fold in females. Cmax also increased about 5-fold from day 1 to day 7 in males. These increases in blood concentrations and AUC's are likely due to enzyme inhibition. Results obtained from female rats on days 1, 4 and 7 suggest that metabolic changes probably occur after the 4th day of dosing. Therefore, chronic MRZ treatment affected its pharmacokinetics and hepatic metabolizing enzyme activities in rats.

Moricizine: pharmacodynamic, pharmacokinetic, and therapeutic profile of a new antiarrhythmic.

Moricizine (Ethmozine) is a phenothiazine derivative recently approved in the United States for the treatment of malignant ventricular arrhythmias. Moricizine closely resembles group IA antiarrhythmic agents in the intensity of its effect on the sodium channel, but it differs from the IA subclass in that it shortens the action potential duration in ventricular tissue. Moricizine suppresses frequent ventricular premature depolarizations and nonsustained ventricular tachycardia in 60% to 70% of patients, and it suppresses induced ventricular tachycardia in 15% to 25% of patients. It is well tolerated, with a low incidence of adverse effects. The suggested dosage is 600 to 900 mg per day in three divided doses. Treatment of arrhythmias with prognostic significance should be initiated in the hospital, and monitored with electrophysiologic studies. Additional clinical experience is needed to better define moricizine's role in antiarrhythmic therapy.

Influence of food on the oral absorption and bioavailability of moricizine.

Moricizine, a unique Class I antiarrhythmic agent, was orally administered with and without a meal to 24 healthy male subjects to determine the effect of food on moricizine absorption and bioavailability. Relative to the fasting state, a standardized breakfast delayed the time to peak plasma moricizine concentration (1.2 vs. 0.9 hr; P less than .03) and lowered peak plasma moricizine concentration by 24% (0.55 vs. 0.72 microgram/mL; P less than .03). Bioavailability, as measured by area under the plasma moricizine concentration versus time curve, was not significantly altered by the meal.

Dose proportionality of moricizine after escalating multiple doses in healthy volunteers.

This study was designed to determine the dose linearity and proportionality of moricizine after multiple-dose administrations of 450 to 900 mg/day. The study design was an open-label, four-treatment, four-period sequentials escalating dose. Twelve subjects each received multiple doses of 150, 200, 250, and 300 mg of moricizine every 8 hours during 7 days of treatment. Blood samples for pharmacokinetic determinations were obtained on day 7 of each treatment period during an 8-hour time interval. Cmin determinations were also made on specific days of each treatment period. The AUC tau (area under the curve from time 0 to 8 hours), Cmax, and Cmin parameters were all normalized to the 250-mg (750 mg/day) dose. No statistically significant differences were seen in these parameters at the four treatment levels. It was concluded that moricizine follows first-order or linear pharmacokinetics after multiple dosing and exhibits dose proportional pharmacokinetics in the dosage-range studies. This range corresponds to the clinically useful dosage range.

Moricizine: a new class I antiarrhythmic.

The chemistry, pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage of the Class I antiarrhythmic agent moricizine hydrochloride are reviewed. Moricizine is chemically similar to the phenothiazines but does not appear to block dopaminergic receptors. Its major electrophysiologic actions are a concentration-dependent decrease in maximum rate of phase 0 depolarization; increased rates of phase 2 and 3 repolarization, decreased action potential duration, and decreased effective refractory period. Moricizine causes a dose-related prolongation of the PR interval and of AV nodal, infranodal, and intraventricular conduction times but has little effect on ventricular repolarization. The antiarrhythmic and electrophysiologic effects are not correlated with plasma concentrations of the drug or its metabolites. Moricizine reduces the occurrence of ventricular premature contractions (VPCs), couplets, and nonsustained ventricular tachycardia. It appears to suppress symptomatic nonsustained ventricular tachycardia, sustained ventricular tachycardia, and ventricular fibrillation or flutter. Moricizine appears to be as effective as quinidine and more effective than disopyramide, propranolol, and imipramine but less effective than flecainide and encainide at reducing VPCs. Moricizine continues to be evaluated in the Cardiac Arrhythmia Suppression Trial, which was designed to assess the long-term benefit of arrhythmia suppression in patients with left ventricular dysfunction after myocardial infarction. Moricizine seems to be better tolerated than quinidine, disopyramide, and imipramine and to have less proarrhythmic potential than flecainide or encainide. Noncardiac adverse effects include dizziness, nausea, and headache. Cimetidine appears to decrease moricizine clearance, and decreased theophylline clearance has been reported in subjects given moricizine. The usual adult dosage of moricizine hydrochloride is 600-900 mg/day given in three divided doses; an every-12-hour regimen may be used in some patients. Because of the risk of proarrhythmic effects, indications are limited to treatment of documented life-threatening arrhythmias. Moricizine will compete with other agents as first-line therapy for life-threatening arrhythmias.