Effect of CYP2D6 genetic polymorphism on peak propafenone concentration: no significant effect of CYP2D6*10.

Aim: The study aims to investigate the clinical implication of nonfunctional poor metabolizer (PM) alleles and intermediate metabolizer (IM) alleles of CYP2D6, including the CYP2D6*10 allele which shows substrate-dependent decrease in enzymatic activity, in antiarrhythmic therapy using propafenone. Materials & methods: We examined serum propafenone concentrations and metabolic ratio, which was expressed as serum concentrations of propafenone to 5-hydroxypropafenone, in 66 Japanese patients with tachyarrhythmias. Results: The peak propafenone concentration and metabolic ratio in CYP2D6 PM allele carriers were higher than those in extensive metabolizer (EM)/EM, EM/IM and IM/IM genotype groups. Conclusion: Results suggest that CYP2D6 PM alleles affect peak propafenone concentration, but the CYP2D6 IM allele CYP2D6*10 has no clinical implication in propafenone dosing.

Beyond the Michaelis-Menten: Accurate Prediction of In Vivo Hepatic Clearance for Drugs With Low KM.

Clearance (CL) is the major pharmacokinetic parameter for evaluating systemic exposure of drugs in the body and, thus, for developing new drugs. To predict in vivo CL, the ratio between the maximal rate of metabolism and Michaelis-Menten constant (Vmax /KM estimated from in vitro metabolism study has been widely used. This canonical approach is based on the Michaelis-Menten equation, which is valid only when the KM value of a drug is much higher than the hepatic concentration of the enzymes, especially cytochrome P450, involved in its metabolism. Here, we find that such a condition does not hold for many drugs with low KM , and, thus, the canonical approach leads to considerable error. Importantly, we propose an alternative approach, which incorporates the saturation of drug metabolism when concentration of the enzymes is not sufficiently lower than KM . This new approach dramatically improves the accuracy of prediction for in vivo CL of high-affinity drugs with low KM . This indicates that the proposed approach in this study, rather than the canonical approach, should be used to predict in vivo hepatic CL for high-affinity drugs, such as midazolam and propafenone.

Regioselective hydroxylation of an antiarrhythmic drug, propafenone, mediated by rat liver cytochrome P450 2D2 differs from that catalyzed by human P450 2D6.

1. Propafenone, an antiarrhythmic drug, is a typical human cytochrome P450 (P450) 2D6 substrate used in preclinical studies. Here, propafenone oxidation by mammalian liver microsomes was investigated in vitro. 2. Liver microsomes from humans and marmosets preferentially mediated propafenone 5-hydroxylation, minipig, rat and mouse livers primarily mediated 4'-hydroxylation, but cynomolgus monkey and dog liver microsomes differently mediated N-despropylation. 3. Quinine, ketoconazole or anti-P450 2D antibodies suppressed propafenone 4'/5-hydroxylation in human and rat liver microsomes. Pretreatments with ß-naphthoflavone or dexamethasone increased N-despropylation in rat livers. 4. Recombinant rat P450 2D2 efficiently catalysed propafenone 4'-hydroxylation in a substrate inhibition manner, comparable to rat liver microsomes, while human P450 2D6 displayed propafenone 5-hydroxylation. Human and rat P450 1A, 2C and 3A enzymes mediated propafenone N-despropylation with high capacities. 5. Carbon-4' of propafenone docked favourably into the active site of P450 2D2 based on an in silico model; in contrast, carbon-5 of propafenone docked into human P450 2D6. 6. These results suggest that the major roles of individual P450 2D enzymes in regioselective hydroxylations of propafenone differ between human and rat livers, while the minor roles of P450 1A, 2C and 3A enzymes for propafenone N-despropylation are similar in livers of both species.

Optimal sampling time and clinical implication of the SCN5A promoter haplotype in propafenone therapeutic drug monitoring.

PURPOSE: The clinical usefulness of therapeutic drug monitoring (TDM) of propafenone, a sodium channel blocker, has been unclear due to the lack of information regarding optimal blood sampling time and therapeutic concentration range. Antiarrhythmic effects of sodium channel blockers are affected by the activity of the cardiac sodium channel (SCN5A). We investigated the optimal sampling time and the clinical implication of the SCN5A promoter haplotype in propafenone TDM. METHODS: We evaluated serum concentrations of propafenone, the SCN5A promoter haplotype, and antiarrhythmic efficacy in 55 patients with supraventricular tachy-arrhythmias. Blood samples obtained 1.5-6 and 10-24 h after the last dose were categorized as peak and trough samples, respectively. RESULTS: The peak propafenone concentration was significantly higher in effectively treated patients than that in patients showing insufficient response (337 ± 213 vs. 177 ± 93 ng/mL, P = 0.005), but the trough propafenone concentration was not significantly different between the two groups (68 ± 48 vs. 42 ± 36 ng/mL). Clinically relevant propafenone efficacy was achieved significantly more often in SCN5A haplotype B carriers than in wild-type haplotype A homozygotes (90 vs. 60%, P < 0.05). Among the haplotype A homozygotes, peak propafenone concentration was higher in effectively treated patients than that in patients showing insufficient response (299 ± 177 vs. 177 ± 93 ng/mL, P = 0.061). CONCLUSION: The present study found that antiarrhythmic efficacy of propafenone was associated with peak propafenone concentration rather than trough concentration and was affected by the SCN5A promoter haplotype.

Propafenone quantification in human plasma by high-performance liquid chromatography coupled with electrospray tandem mass spectrometry in a bioequivalence study
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Propafenone is an antiarrhythmic drug applied to ventricular arrhythmias, initially recognized as a sodium channel blocker. This study aims to evaluate the bioequivalence of two propafenone formulations (300 mg tablet) in healthy subjects under non-fasting conditions. The study was conducted as an open, randomized, 2-period design with a 2-sequence (RT, TR) with a 1-week washout interval. The subjects were selected for the study after having their health status previously assessed by a clinical evaluation and laboratory tests (biochemical and hematological parameters, and urinalysis). Debrisoquine phenotype of healthy subjects was determined by analysis of urinary excretion of debrisoquine and its major metabolite, 4-hydroxydebrisoquine. A single propafenone tablet (300 mg) was given in each occasion. Plasma propafenone concentrations were analyzed by liquid chromatography coupled to tandem mass spectrometry (HPLC/MS/MS) with positive ion electrospray ionization using multiple reactions monitoring (MRM). The geometric mean and 90% confidence intervals (CI) of propafenone/Ritmonorm® (T/R) percent ratio were 100.44% (88.39 - 114.13%) for AUClast, 99.84% (90.31 - 110.36%) for AUCinf, and 99.30% (90.08 - 109.47%) for Cmax. Since the 90% CI for Cmax, AUClast, and AUCinf ratios were all inside the 80 - 125% interval proposed by the US Food and Drug Administration Agency, it was concluded that the propafenone formulation elaborated by Biolab Sanus Farmacêutica Ltda. is bioequivalent to Ritmonorm® formulation for both the rate and the extent of absorption. The drug was well tolerated by the subjects, indicating that it is safe to perform propafenone bioequivalence studies in healthy subjects with intermediate/extensive metabolism.
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Simultaneous determination of serum propafenone and its metabolites using high-performance liquid chromatography.

Propafenone, a class Ic antiarrhythmic agent, is metabolized to 5-hydroxypropafeone (5-OHP) and N-depropylpropafenone (NDPP). Simultaneous determination of serum propafenone and its metabolites was performed using HPLC equipped with a conventional octadecylsilyl silica column and ultraviolet detector. The wavelength was set at 250 nm. Propafenone and its metabolites in the serum were extracted using diethyl ether. The mobile phase solution, comprising 1-pentanesulfonic acid sodium salt (0.1 m), acetonitrile and acetic acid (280:185:2.5, v/v/v), was pumped at a flow rate of 1 mL/min. The recoveries of propafenone, 5-OHP and NDPP were greater than 85, 82 and 60%, respectively, with the coefficients of variation (CVs) less than 5.4, 1.9 and 2.9%, respectively. The calibration curves were linear for a concentration range of 12.5-1500 ng/mL for propafenone and 2-500 ng/mL for 5-OHP and NDPP (r > 0.999). CVs in the intraday assays were 1.0-3.8% for propafenone, 0.6-2.0% for 5-OHP and 0.6-1.7% for NDPP. CVs in interday assays were 1.3-7.7% for propafenone, 1.1-6.5% for 5-OHP and 5.4-8.0% for NDPP. The present HPLC method can be used to assess the disposition of propafenone and its metabolites for pharmacokinetic studies and therapeutic drug monitoring of propafenone.

A Sensitive and Rapid LC-MS-MS Method for Simultaneous Determination of Propafenone and Its Active Metabolite 5-Hydroxypropafenone in Human Plasma and Its Application in a Pharmacokinetic Study.

A simple and rapid high-performance liquid chromatography tandem mass spectrometry method for the determination of propafenone (PPF) and its active metabolite 5-hydroxypropafenone (5-OHP) in human plasma was developed and validated. This new method was linear and allowed simultaneous quantification of PPF and 5-OHP at a lower level of 0.5 ng/mL. The aliquot of 200 µL plasma sample was simply treated with 4-fold methanol to deproteinize the plasma. The chromatographic separation was achieved on a Hedera ODS-2C18 analytical column with the mobile phase of methanol and 5 mM ammonium acetate solution containing 0.2% formic acid (pH 3.2) (68:32, v/v) at a flow rate of 0.4 mL/min. Quantitation of the analytes was achieved by multiple reaction monitoring under positive ionization mode. The method was successfully applied to a pharmacokinetic study of PPF and 5-OHP in healthy Chinese volunteers. After oral administration of a single dose of 425 mg PPF hydrochloride sustained-release capsule, the maximum peak plasma concentration (Cmax) of PPF was 210.9 ± 141.9 ng/mL with a Tmax of 6 ± 1 h, the Cmax of 5-OHP was 129.6 ± 65.4 ng/mL with a Tmax of 7 ± 2 h. The area under plasma concentration-time curve (AUC0-36) of PPF was 1610 ± 1309 ng·h/mL with a t1/2 of 4.6 ± 1.1 h, the AUC0-36 of 5-OHP was 1446 ± 754 ng·h/mL with a t1/2 of 7.6 ± 1.6 h.

A sensitive quantitative assay for the determination of propafenone and two metabolites, 5-hydroxypropafenone and N-depropylpropafenone, in human K2EDTA plasma using LC-MS/MS with ESI operated in positive mode.

Propafenone is a potent antiarrhythmic agent; clinically propafenone has been used for a number of cardiac arrhythmias because it possesses multiple modes of action, via beta adrenergic receptor blockade and calcium antagonistic activity. Propafenone (PPF) exhibits extensive saturable presystemic biotransformation (first-pass effect) resulting in two active metabolites: 5-hydroxypropafenone (5-OH PPF) formed by CYP2D6 and N-depropylpropafenone (NDP) formed by both CYP3A4 and CYP1A2 enzymes. A specific and sensitive LC-MS/MS method was developed and validated for quantitation of PPF, 5-OH PPF and NDP using turboion spray in a positive ion mode. A solid-phase extraction was employed for the extraction from human plasma. Chromatographic separation of analytes was achieved using an ACE-5 C8 (50 × 4.6 mm) column with a gradient mobile phase comprising ammonium acetate containing 0.01% TFA in purified water and acetonitrile. The retention times achieved were 1.36, 1.23, 1.24 min and 1.34 min for PPF, 5-OH PPF, NDP and IS (carbamazepine), respectively. Quantitation was performed by monitoring multiple reaction monitoring transition pairs of m/z 342.30 to m/z 116.20, m/z 358.30 to m/z 116.20, m/z 300.30 to m/z 74.20 and m/z 237.20 to m/z 194.10, respectively. The developed method was validated for various parameters. The calibration curves of PPF and 5-OH PPF showed linearity from 1 to 500 ng/mL, with a lower limit of quantitation of 1.0 ng/mL and for NDP linearity from 0.1 to 25 ng/mL with a lower limit of quantitation of 0.1 ng/mL. The bias and precision for intra- and-inter batch assays were <10 and 5%, respectively. The developed assay was used to evaluate pharmacokinetic properties of propafenone and its major metabolites in healthy human subjects.

Effect of CYP2D6 polymorphisms on the pharmacokinetics of propafenone and its two main metabolites.

AIM OF THE STUDY: Propafenone (PPF) is an antiarrhythmic drug, metabolized mainly by CYP2D6 to 5-hydroxypropafenone (5OH-PPF) and by CYP3A4 to norpropafenone (NOR-PPF). CYP2D6 shows a high degree of genetic polymorphism which is associated with diminished antiarrhythmic efficacy or cardiac seizures/cardiotoxicity. This study aimed to investigate the effect of the CYP2D6 polymorphism on the pharmacokinetics of PPF and its two main metabolites. The usefulness of PPF/5OH-PPF ratio for CYP2D6 phenotyping in healthy adults was also evaluated. METHODS: Twelve healthy volunteers, 3 poor metabolizers (PM), 2 intermediate metabolizers (IM) and seven extensive metabolizers (EM) received an oral dose of PPF. Concentrations of PPF and its metabolites were analyzed in serum samples over 27h. RESULTS: The PPF/5OH-PPF ratio distinguished EMs from PMs, but not from IMs. In PMs, the mean transit time (MTT) values were almost the same for PPF and NOR-PPF and much higher than those of EMs and IMs. 5OH-PPF was not detected in EMs. Mean MTT values of 5OH-PPF and NOR-PPF in IMs were 5.27- and 1.52-fold higher than those of EMs. CONCLUSION: A single time point serum PPF-MR approach is a useful tool to identify PMs. CYP2D6 polymorphism significantly affects the pharmacokinetics of PPF and its two metabolites.

Anti-arrhythmic Medication Propafenone a Potential Drug for Alzheimer's Disease Inhibiting Aggregation of Aß: In Silico and in Vitro Studies.

Alzheimer's disease (AD) is the most common form of dementia caused by the formation of Aß aggregates. So far, no effective medicine for the treatment of AD is available. Many efforts have been made to find effective medicine to cope with AD. Curcumin is a drug candidate for AD, being a potent anti-amyloidogenic compound, but the results of clinical trials for it were either negative or inclusive. In the present study, we took advantages from accumulated knowledge about curcumin and have screened out four compounds that have chemical and structural similarity with curcumin more than 80% from all FDA-approved oral drugs. Using all-atom molecular dynamics simulation and the free energy perturbation method we showed that among predicted compounds anti-arrhythmic medication propafenone shows the best anti-amyloidogenic activity. The in vitro experiment further revealed that it can inhibit Aß aggregation and protect cells against Aß induced cytotoxicity to almost the same extent as curcumin. Our results suggest that propafenone may be a potent drug for the treatment of Alzheimer's disease.

Propafenone enhances the anticonvulsant action of classical antiepileptic drugs in the mouse maximal electroshock model.

BACKGROUND: Antiarrhythmic and antiepileptic drugs share some mechanisms of actions. Therefore, possibility of interactions between these in epileptic patients with cardiac arrhythmias is quite considerable. Herein, we attempted to assess interactions between propafenone and four conventional antiepileptic drugs: carbamazepine, valproate, phenytoin and phenobarbital. METHODS: Effects of propafenone on seizures were determined in the electroconvulsive threshold test in mice. Interactions between propafenone and antiepileptic drugs were estimated in the model of maximal electroshock. Motor coordination was evaluated in the chimney test, while long-term memory in the passive-avoidance task. Brain concentrations of antiepileptics were determined by fluorescence polarization immunoassay. RESULTS: Propafenone up to 50mg/kg did not affect the electroconvulsive threshold, significantly enhancing this parameter at doses of 60-90mg/kg. Applied at its subthreshold doses, propafenone potentiated the antielectroshock action of all four tested classical antiepileptics: carbamazepine, valproate, phenytoin, and phenobarbital. Propafenone alone and in combinations with antiepileptics impaired neither motor performance nor long-term memory in mice. Propafenone did not change brain concentration of phenytoin and phenobarbital; however, it significantly decreased brain levels of carbamazepine and increased those of valproate. CONCLUSIONS: Propafenone exhibits its own anticonvulsant effect and enhances the action of classical antiepileptic drugs against electrically induced convulsions in mice. Further investigations are required to determine the effect of propafenone on antiepileptic therapy in humans.

DDPH, a novel antihypertensive agent, is a potential dual inhibitor of hepatic CYP2D and CYP3A.

DDPH (1-(2, 6-dimethylphenoxy)-2-(3, 4-dimethoxyphenylethylamino) propane hydrochloride) is a promising novel antihypertensive agent, with potent antihypertensive, neuroprotective and cardioprotective effects. This study aimed to investigate the effects of DDPH on the expression and activity of hepatic cytochrome P450 (CYP) isoforms and evaluate the metabolic drug-drug interactions of DDPH with propafenone. Our results showed that orally administered DDPH (12.5-50 mg/kg/d) for 7 days significantly inhibited CYP2D1 and CYP3A1 activity and mRNA and protein expression but weakly increased CYP1A2 activity and expression in rats. Enzyme kinetics studies showed that DDPH was a competitive inhibitor of CYP2D1 and mixed inhibitor of CYP3A1 in rat liver microsomes with Ki values of 3.70 ± 0.42 µM and 4.79 ± 1.10 µM respectively. With human liver microsomes, DDPH was a noncompetitive inhibitor of CYP2D6 (Ki = 0.85 ± 0.06 µM) and mixed inhibitor of CYP3A (Ki = 2.15 ± 0.41 µM). Further in vivo study showed that oral administration of DDPH (12.5-50 mg/kg/d) for 7 days in rats significantly increased the area under the plasma concentration-time curve (AUC) of propafenone by 25.4%-63.9%, with a concomitant decrease in the plasma clearance. In conclusion, the results indicated that DDPH inhibited CYP2D and CYP3A activities and down-regulated their protein expression and mRNA transcription. DDPH might cause metabolic drug-drug interactions through modulation of the activity and expression of CYP2D and CYP3A. This information could be important in the prediction of possible drug-drug interactions as well as for the effective therapy and the limitation of toxicity of DDPH in clinical practice.

Propafenone shows class Ic and class II antiarrhythmic effects.

AIMS: Propafenone is a well-known Class Ic antiarrhythmic agent. It has the typical chemical structure of a beta-blocker, but human studies on its beta-blocking effects revealed conflicting results. METHODS AND RESULTS: Twelve healthy males received single oral doses of 600 mg propafenone and placebo according to a randomized, double-blind, placebo-controlled, cross-over protocol. Four hours following drug intake, heart rate and blood pressure were measured, and plasma concentrations of propafenone were determined at rest, during exercise and after recovery. At exercise, propafenone significantly decreased heart rate (-6%, P < 0.05), systolic blood pressure (-6%, P < 0.05), and the rate-pressure product (-11%, P < 0.05). Plasma concentrations of propafenone increased during exercise (+23%, P < 0.05) and decreased during recovery (-33%, P < 0.05). CONCLUSION: Both effects on heart rate and blood pressure as well as the changes of plasma concentrations of propafenone during exercise represent two particular features of beta-blockers. Therefore, we conclude that propafenone is both a Class Ic and a Class II antiarrhythmic agent, and 600 mg propafenone, i.e. the dose recommended in current guidelines for cardioversion of paroxysmal atrial fibrillation, cause clinically significant beta-blockade. Thus, single oral doses of 600 mg propafenone appear also suitable for cardioversion of paroxysmal atrial fibrillation in patients with structural heart disease since beta-blockers are explicitly indicated in the treatment of both coronary artery disease and heart failure.

Bioequivalência de cloridrato de propafenona 300mg em comprimido revestido em administração pós-prandial em adultos saudáveis / Bioequivalence of propafenone hydrochloride 300mg film coated tablets in healthy adults

OBJETIVO: Avaliar a bioequivalência de duas formulações de cloridrato de propafenona 300mg em comprimido revestido.MÉTODOS: Estudo randomizado, cruzado, aberto, com dois tratamentos, duas sequências e quatro períodos com 60 participantes sadios de ambos os sexos. Os voluntários foram internados em quatro oportunidades durante 24 horas; em cada período, os sujeitos receberam a formulação teste ou a formulação referência, em regime pós-prandial. Foram coletadas 23 amostras de sangue após administração da droga para determinação plasmática da propafenona. Para quantificação da droga, foi utilizada técnica de cromatografia líquida acoplada à espectrometria de massas sequencial. RESULTADOS: As formulações foram consideradas clinicamente bem toleradas. A concentração máxima e a área sob a curva de zero a 36 horas foram comparadas: a média geométrica da razão entre as formulações teste e referência para concentração máxima foi de 110,16%, com intervalo de confiança de 99,44% a 122,04% e coeficiente de variação de 33,95%. A média geométrica da razão entre as formulações teste e referência para a área sob a curva de zero a 36 horas foi de 107,92%, com intervalo de confiança de 99,58% a 116,96% e coeficiente de variação de 26,39%. A média geométrica da razão entre o medicamento teste e referência para área sob a curva de zero ao infinito foi de 107,12%, com intervalo de confiança de de 99,11% a 115,78% e coeficiente de variação de 25,48%. CONCLUSÃO: As formulações teste e referência foram estatisticamente bioequivalentes, de acordo com sua taxa e extensão de absorção.

OBJECTIVE: To evaluate the bioequivalence of two 300mg profanone hydrochloride coated tablets. METHODS: Randomized, cross-over, openstudy, with two treatments, two sequences, and four periods with 60 healthy participants of both genders. The volunteers were admitted in four opportunities over 24 hours; on each period, the subjects received a test formulation, or a reference formulation, in a postprandial administration. Twenty-three samples of blood were collected after oral administration of the drug for determining plasma level of propafenone. Liquid chromatography-mass spectrometry was used for quantifying propafenone. RESULTS: The formulations were considered clinically well tolerated. The maximum concentration and the area under the curve from zero to 36 hours were compared: the geometric mean of the ratio between the test and reference formulations for maximum concentration was 110.16%, with confidence interval of 99.44% - 122.04%), coefficient of variation of 33.95%. The geometric mean of the ratio between the test and reference formulations for the area under the curve of zero to 36 hours was 107.92%, with confidence interval of 99.58% - 116.96%, and coefficient of variation of 26.39%. The geometric mean of the ratio between the formulations for area under the curve of zero to infinitum as 107.12% with confidence interval of 99.11% - 115.78%),and coefficient of variation of 25.48%. CONCLUSION: According to the rate and extension of absorption, the test and reference formulations are statistically bioequivalent.

Novel sustained-release of propafenone through pellets: preparation and in vitro/in vivo evaluation.

In this study, an extrusion-spheronization method was applied successfully to fabricate propafenone hydrochloride (PPF) sustained-release pellets. Using scanning electron microscopy, it was shown that the PPF pellets had a mean size of approximately 950 µm with a spherical shape. The in vitro release profiles indicated that the release of PPF from the pellets exhibited a sustained release behavior. The relatively high correlation coefficient (r) values obtained from the analysis of the amount of the drug released versus the square root of time indicated that the release followed a zero order kinetic model. A similar phenomenon was also observed in a pharmacokinetic study in dogs, in which the area under the curve (AUC) of the pellet formulation was 1.2-fold higher than that of PPF tablets. The present work demonstrated the feasibility of controlled delivery of PPF utilizing microcrystalline cellulose (MCC)-based pellets.

Tratamiento antiarrítmico farmacológico en fase crónica de la fibrilación auricular / Long-term antiarrhythmic drug therapy for atrial fibrillation

El tratamiento antiarrítmico crónico de la fibrilación auricular ha experimentado pocos cambios en los últimos años hasta la irrupción de la dronedarona. Su papel probablemente quedará restringido a pacientes con fibrilación auricular paroxística o persistente sin clínica de insuficiencia cardiaca asociada. La decisión más importante que debe adoptar el cardiólogo sigue siendo si luchar por mantener el ritmo cardiaco o simplemente mantener una frecuencia cardiaca adecuada. La primera opción es más recomendable para pacientes sintomáticos sin demasiada cardiopatía estructural; la segunda, para pacientes poco sintomáticos o asintomáticos, de edad avanzada y con cardiopatía estructural asociada que haga previsible que el ritmo sinusal no se mantenga. La combinación con tratamientos no farmacológicos, como la ablación, actualmente es una realidad que probablemente será más notable aún en un futuro cercano (AU)

Long-term pharmacologic treatment of atrial fibrillation underwent few changes in the years before the recent introduction of dronedarone. Use of this drug is restricted to patients with paroxysmal or persistent atrial fibrillation who are scheduled for electrical cardioversion and who show no signs of associated heart failure. The most important decision facing the cardiologist is still whether to attempt to maintain sinus rhythm or simply to maintain an adequate heart rate. The first option is preferred for symptomatic patients without substantial structural heart disease; the second is preferred for patients with no or few symptoms and those of advanced age who have associated structural heart disease which makes it unlikely that sinus rhythm can be maintained. The combination of pharmacologic treatment with nonpharmacologic treatment, such as ablation, is today a real option that will probably become more widely used in the near future (AU)

Combined administration of quinidine and propafenone for atrial fibrillation: the CAQ-PAF study.

Propafenone and its 5-hydroxy metabolite exhibit different electrophysiological properties. Objectives of the CAQ-PAF study were (1) to develop a strategy favoring propafenone instead of 5-hydroxypropafenone in plasma following oral administration of propafenone and (2) to evaluate the potential of low-dose quinidine to chronically inhibit CYP2D6. Patients (n = 102) with atrial fibrillation received propafenone 150 mg 3 times daily with either quinidine 100 mg twice daily or placebo. Throughout the study (follow-up, 199 ± 155 days), quinidine successfully inhibited CYP2D6: propafenone concentrations were 3 times higher in patients receiving quinidine (1033 ± 611 ng/mL vs 328 ± 229 ng/mL; P < .001). Moreover, 80% (n = 10) of patients with propafenone levels greater than 1500 ng/mL were in sinus rhythm at 1 year. In contrast, recurrence of atrial fibrillation occurred in 22 of 23 patients with propafenone levels less than 1000 ng/mL (P < .0001). Thus, chronic inhibition of CYP2D6 is achievable with low-dose quinidine in humans. Increased plasma levels of propafenone may be highly beneficial to prevent recurrence of atrial fibrillation.

Comparative pharmacokinetics between a microdose and therapeutic dose for clarithromycin, sumatriptan, propafenone, paracetamol (acetaminophen), and phenobarbital in human volunteers.

A clinical study was conducted to assess the ability of a microdose (100 µg) to predict the human pharmacokinetics (PK) following a therapeutic dose of clarithromycin, sumatriptan, propafenone, paracetamol (acetaminophen) and phenobarbital, both within the study and by reference to the existing literature on these compounds and to explore the source of any nonlinearity if seen. For each drug, 6 healthy male volunteers were dosed with 100 µg (14)C-labelled compound. For clarithromycin, sumatriptan, and propafenone this labelled dose was administered alone, i.e. as a microdose, orally and intravenously (iv) and as an iv tracer dose concomitantly with an oral non-labelled therapeutic dose, in a 3-way cross over design. The oral therapeutic doses were 250, 50, and 150 mg, respectively. Paracetamol was given as the labelled microdose orally and iv using a 2-way cross over design, whereas phenobarbital was given only as the microdose orally. Plasma concentrations of total (14)C and parent drug were measured using accelerator mass spectrometry (AMS) or HPLC followed by AMS. Plasma concentrations following non-(14)C-labelled oral therapeutic doses were measured using either HPLC-electrochemical detection (clarithromycin) or HPLC-UV (sumatriptan, propafenone). For all five drugs an oral microdose predicted reasonably well the PK, including the shape of the plasma profile, following an oral therapeutic dose. For clarithromycin, sumatriptan, and propafenone, one parameter, oral bioavailability, was marginally outside of the normally acceptable 2-fold prediction interval around the mean therapeutic dose value. For clarithromycin, sumatriptan and propafenone, data obtained from an oral and iv microdose were compared within the same cohort of subjects used in the study, as well as those reported in the literature. For paracetamol (oral and iv) and phenobarbital (oral), microdose data were compared with those reported in the literature only. Where 100 µg iv (14)C-doses were given alone and with an oral non-labelled therapeutic dose, excellent accord between the PK parameters was observed indicating that the disposition kinetics of the drugs tested were unaffected by the presence of therapeutic concentrations. This observation implies that any deviation from linearity following the oral therapeutic doses occurs during the absorption process.

Trapping and dissociation of propafenone derivatives in HERG channels.

BACKGROUND AND PURPOSE: Human ether-a-go-go related gene (HERG) channel inhibitors may be subdivided into compounds that are trapped in the closed channel conformation and others that dissociate at rest. The structural peculiarities promoting resting state dissociation from HERG channels are currently unknown. A small molecule-like propafenone is efficiently trapped in the closed HERG channel conformation. The aim of this study was to identify structural moieties that would promote dissociation of propafenone derivatives. EXPERIMENTAL APPROACH: Human ether-a-go-go related gene channels were heterologously expressed in Xenopus oocytes and potassium currents were recorded using the two-microelectrode voltage clamp technique. Recovery from block by 10 propafenone derivatives with variable side chains, but a conserved putative pharmacophore, was analysed. KEY RESULTS: We have identified structural determinants of propafenone derivatives that enable drug dissociation from the closed channel state. Propafenone and four derivatives with 'short' side chains were trapped in the closed channel. Five out of six bulky derivatives efficiently dissociated from the channel at rest. One propafenone derivative with a similar bulk but lacking an H-bond acceptor in this region was trapped. Correlations were observed between molecular weight and onset of channel block as well as between pK(a) and recovery at rest. CONCLUSION AND IMPLICATIONS: The data show that extending the size of a trapped HERG blocker-like propafenone by adding a bulky side chain may impede channel closure and thereby facilitate drug dissociation at rest. The presence of an H-bond acceptor in the bulky side chain is, however, essential.

Comparative bioavailability of propafenone after administration of a magistral suspension vs. commercial tablets in healthy volunteers.

Propafenone (CAS 34183-22-7) is an effective antiarrhythmic drug used in children, although in some countries no specific pediatric formulation is available. The aim of this study is to compare the relative bioavailability of a magistral (MAG) preparation of propafenone versus its commercial (COM) presentation in a group of 16 Mexican healthy volunteers. Bioavailability was determined after crossover administration of the drugs, through a randomized two-phase trial. All volunteers had normal hepatic and renal functions, determined clinically at the beginning of the study, and received 150 mg of either COM (tablets) or MAG (suspension). Blood samples were drawn for a 24-h post-dose analysis by HPLC to measure plasma levels of propafenone. Subjects (mean 25.9 +/- 5.3 years and 66.1 +/- 12.4 kg) had the following pharmacokinetic parameters: Cmax 189.9 +/- 20.92 ng/mL, Tmax 1.5 h, AUC 322.4 +/- 36.28 ng x ml(-1) x h for COM. Values for MAG were Cmax 225.8 +/- 24.38 ng/mL, Tmax 1.7 h and AUC 359.3 +/- 27.90 ng x ml(-1) x h. These values yielded a relative bioavailability of 111.42% for MAG compared with COM. No electrocardiographic changes were recorded in any subject with respect to the baseline value, in both treatment schemes. Therefore, propafenone suspension prepared as a magistral formulation may be used as an alternative drug in pediatric patients.