benzofurans and desethylamiodarone

Amiodarone and dronedarone are two clinically important benzofuran derivatives. Amiodarone has been used widely for treating resistant tachyarrhythmias in the past three decades. However amiodarone and its main metabolically active metabolite desethylamiodarone can adversely affect many organs, including the thyroid gland. Amiodarone-induced thyroid disorders are common and often present as a management challenge for endocrinologists. The pathogenesis of amiodarone-induced thyroid dysfunction is complex but the inherent effects of the drug itself as well as its high iodine content appear to play a central role. The non-iodinated dronedarone also exhibits anti-arrhythmic properties but appears to be less toxic to the thyroid. This review describes the biochemistry of benzofuran derivatives, including their pharmacology and the physiology necessary for understanding the cellular mechanisms involved in their actions. The known effects of these compounds on thyroid action are described. Recommendations for management of amiodarone-induced hypothyroidism and thyrotoxicosis are suggested. Dronedarone appears to be an alternative but less-effective anti-arrhythmic agent and it does not have adverse effects on thyroid function. It may have a future role as an alternative agent in patients being considered for amiodarone therapy especially those at high risk of developing thyroid dysfunction but not in severe heart failure.

Topics: Amiodarone; Animals; Anti-Arrhythmia Agents; Benzofurans; Dronedarone; Humans; Hypothyroidism; Receptors, Thyroid Hormone; Thyroid Diseases; Thyroid Gland; Thyrotoxicosis

In an attempt to assess their respective values for purposes of drug monitoring, plasma, red blood cell, atrial, and ventricular concentrations of amiodarone and N-desethylamiodarone (NDA) were measured, in 50 surgical patients, after a single oral dose (30 mg/kg); hemodynamic changes were assessed also. Amiodarone concentration was lower in red blood cells than in plasma and in myocardium. A relationship was found between the red blood cell concentration and plasma or myocardial concentrations of amiodarone (r = 0.79 and r = 0.68, p less than 0.00001). Hemodynamic studies were available in 17 treated patients and 13 control subjects before and at the time of surgery. In control subjects, hemodynamics did not change with time and general anesthesia. Oral amiodarone decreased the cardiac index (p less than 0.05) and heart rate (p less than 0.001) without significant changes in arterial pressure, systemic vascular resistance, or stroke volume index. The increase in capillary wedge pressure was related to amiodarone or NDA plasma, myocardial, and red blood cell concentrations (for amiodarone: r = 0.61, p = 0.006; r = 0.69, p less than 0.001; and r = 0.53, p = 0.02, respectively). We concluded that oral amiodarone impairs hemodynamics and that measurement of the amiodarone plasma concentration rather than the red blood cell concentration is the easiest method of monitoring the drug. However, establishment of the clinical utility of drug monitoring during chronic administration of amiodarone needs further investigation.

Topics: Administration, Oral; Adult; Amiodarone; Arrhythmias, Cardiac; Benzofurans; Blood Pressure; Erythrocytes; Female; Heart Rate; Heart Valves; Hemodynamics; Humans; Male; Middle Aged; Myocardium; Postoperative Complications; Stroke Volume; Vascular Resistance

The clinical efficacy of a low-dosage schedule of amiodarone was tested in 58 patients with severe ventricular arrhythmias refractory to other drug treatments. The initially chosen regimen of 400 mg was effective at the end of the first controlled trial period (after 4 weeks) in 73% of the patients. The responsiveness was maintained with the smaller dosage of 200 mg in 68% of this group. The response was reestablished also in the patients who became nonresponders during the low-dose regimen when they returned to the initial (400-mg) dosage. No relation was found between clinical response and blood levels of amiodarone and of its deethylated metabolite. Adverse effects more often associated with amiodarone therapy were rare. However, careful monitoring of thyroid function allowed the detection in 10% of the patients of biochemically and functionally documented, but clinically silent, cases of hypo- or hyperthyroidism.

Topics: Adolescent; Adult; Aged; Amiodarone; Arrhythmias, Cardiac; Benzofurans; Child; Clinical Trials as Topic; Electrocardiography; Female; Heart Ventricles; Humans; Hyperthyroidism; Hypothyroidism; Male; Middle Aged; Prospective Studies; Systole

Amiodarone.HCl (I), 2-butyl-3-benzofuranyl 4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl ketone hydrochloride, C25H30I2NO3+.Cl-, Mr = 680.78, monoclinic, P2(1)/c, a = 17.124 (2), b = 17.079 (2), c = 9.162 (1) A, beta = 98.37 degrees, V = 2651.2 A3, Z = 4, Dx = 1.71 g cm-3, lambda(Mo K alpha) = 0.7107 A, mu = 24.73 cm-1, F(000) = 1332, T = 294 K, R = 6.6% for 5515 data; desethyl-amiodarone.HCl (II), 2-butyl-3-benzofuranyl 4-[2-(ethylamino)ethoxy]-3,5-diiodophenyl ketone hydrochloride, C23H26I2NO3+.Cl-, Mr = 654.74, monoclonic, P2(1)/c, a = 23.867 (2), b = 10.134 (1), c = 10.287 (2) A, beta = 93.91 (2) degrees, V = 2482.5 A3, Z = 4, Dx = 1.75 g cm-3, lambda(Mo K alpha) = 0.07107 A, mu = 26.37 cm-1, F(000) = 1276, T = 294 K, R = 5.7% for 5916 data; benziodarone (III), 2-ethyl-3-benzofuranyl 4-hydroxy-3,5-diiodophenyl ketone, C17H12I2O3, Mr = 518.09, monoclinic, P2(1)/n, a = 17.564 (2), b = 8.294 (1), c = 11.587 (2) A, beta = 93.20 (2) degrees, V = 1685.55 A3, Z = 4, Dx = 2.04 g cm-3, lambda(Mo K alpha) = 0.7101 A, mu = 36.99 cm-1, F(000) = 976, T = 294 K, R = 6.2% for 4311 data.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amiodarone; Anti-Arrhythmia Agents; Benzofurans; Molecular Conformation; Stereoisomerism; Structure-Activity Relationship; Thyroxine

Topics: Amiodarone; Benzofurans; Biological Availability; Drug Interactions; Half-Life; Humans; Kinetics; Tissue Distribution

Topics: Amiodarone; Benzofurans; Cardiomyopathy, Hypertrophic; Humans; Long-Term Care; Photosensitivity Disorders; Sleep Wake Disorders

Topics: Amiodarone; Benzofurans; Humans; Liver; Liver Function Tests; Radiography

Although amiodarone is effective for the suppression of complex ventricular arrhythmias, a major problem with its use is the long delay between the initiation of therapy and the onset of effective suppression of arrhythmia. To test the hypothesis that rapid loading with oral amiodarone to a target serum concentration can overcome much of this delay, eight patients with refractory, sustained, hemodynamically compromising ventricular arrhythmias and 10 patients with potentially life-threatening ventricular arrhythmias were treated with a flexible, very high dose, oral loading protocol (800 to 2000 mg two to three times a day). Dosage was adjusted on the basis of amiodarone serum concentrations to maintain the trough serum concentrations between 2.0 and 3.0 micrograms/ml. Comparison of 24 hr Holter electrocardiograms obtained before and during therapy revealed statistically significant reductions in premature ventricular complexes (PVCs) and paired PVCs beginning the first day of therapy and a reduction in ventricular tachycardia (VT) beginning the second day. By day 2, four of eight patients with sustained VT and six of 10 patients with nonsustained VT showed no VT. Pulmonary arterial catheterization during the first 24 hr (mean amiodarone dose 3933 mg) revealed no significant hemodynamic alterations. Minor side effects were common (10 patients) but major side effects were rare (one patient). High-dose oral loading with amiodarone utilizing serum concentration guidelines is a safe and effective method of rapidly controlling life-threatening arrhythmias in selected patients.

Topics: Administration, Oral; Amiodarone; Arrhythmias, Cardiac; Benzofurans; Drug Administration Schedule; Electrocardiography; Follow-Up Studies; Heart Rate; Heart Ventricles; Hemodynamics; Humans; Kinetics

We describe a rapid, simplified isocratic "high-performance" liquid-chromatographic method for simultaneous measurement of the antiarrhythmic drug amiodarone and its major metabolite, desethylamiodarone, in small volumes of sera (100 microL). Compared with liquid-liquid extraction, the solid-phase method of extraction saves time and glassware and improves reproducibility for small sample volumes. Amiodarone and desethylamiodarone could be measured at concentrations as low as 250 micrograms/L. Standard curves for the drug and metabolite are linear over the range of concentrations found in our patients. Within-run CVs (n = 6) ranged from 2.7% to 4.5% for amiodarone and from 4.0% to 5.7% for desethylamiodarone over the range of 250 to 4000 micrograms/L. Between-run CVs (n = 12) were 8.3% and 5.7% for amiodarone and desethylamiodarone, respectively. Commonly used cardiovascular medications do not interfere with the assay.

Topics: Amiodarone; Benzofurans; Chromatography, High Pressure Liquid; Humans

Thirty-eight patients with refractory supraventricular and ventricular tachyarrhythmias were administered a mean oral dosage of 400 mg amiodarone daily (200-600 mg). A high-pressure liquid chromatography method was used to measure serum concentrations of amiodarone and its metabolite desethylamiodarone after one week, one month, three months, and then at 6-month intervals. In 24 patients subcutaneous fatty tissue concentrations were also measured. The mean follow-up was 9 months (4 days to 29 months). A linear correlation was found between amiodarone and its metabolite in serum (r = 0.56, p less than 0.001) as well as in subcutaneous fatty tissue (r = 0.67, p less than 0.001). While serum concentrations were dose dependent, tissue concentrations accumulated during chronic therapy (p less than 0.01, both). Clinical efficacy was achieved in 84% of the patients. No statistically significant difference was found between responders and non-responders as regards serum and subcutaneous fatty tissue concentrations. Side effects of amiodarone occurred in 63%. The incidence of adverse effects was related to significantly higher serum and subcutaneous fatty tissue concentrations of amiodarone and its metabolite (p less than 0.001, both). Thus, although the determination of serum and subcutaneous fatty tissue concentrations does not seem to be helpful for assessing clinical efficacy of this antiarrhythmic drug, these values may predict the occurrence of adverse effects.

Topics: Adipose Tissue; Adult; Aged; Amiodarone; Benzofurans; Biotransformation; Dose-Response Relationship, Drug; Electrocardiography; Female; Follow-Up Studies; Humans; Kinetics; Male; Middle Aged; Tachycardia

The time to onset of action of amiodarone is often long in patients treated for arrhythmias; one reason might be a slow entry of the drug into the target organ, the heart. Amiodarone and desethylamiodarone, its active metabolite, were measured in the plasma, atrial tissue and pericardial fat of patients undergoing cardiac surgery. Two groups were studied: patients treated with amiodarone for less than 28 days (short-term group) and those treated for 28 days or more (long-term group). Plasma levels of amiodarone in the two groups were not different, whereas levels of desethylamiodarone were significantly higher in the long-term group. Average concentrations of amiodarone in the atrium were higher with longer treatment periods (30.2 +/- 5.6 versus 13.2 +/- 2.5 micrograms/g wet weight of tissue); the same was true for desethylamiodarone (40.3 +/- 7.7 versus 15.7 +/- 3.7 micrograms/g). Amiodarone concentrations in fat were also significantly higher in the long-term than in the short-term group. Atrium/plasma concentration ratios of desethylamiodarone were higher than those of amiodarone, whereas fat plasma concentration ratios of desethylamiodarone were lower. In conclusion, the equilibration of amiodarone and desethylamiodarone concentrations between myocardium and plasma appears to occur slowly in patients undergoing long-term treatment with amiodarone.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adipose Tissue; Adult; Aged; Amiodarone; Arrhythmias, Cardiac; Benzofurans; Cardiac Surgical Procedures; Heart Atria; Humans; Kinetics; Middle Aged; Myocardium; Time Factors

We hypothesized that one of the reasons for the particular susceptibility of the lung toward the adverse effects from the antiarrhythmic agent amiodarone (A) could be a high pulmonary accumulation of this drug. This hypothesis was tested using the isolated perfused lungs of Fischer 344 and Sprague-Dawley rats and New Zealand White rabbits. Uptake of a 3 microM starting concentration of a mixture of A and [14C]A by the lung occurred rapidly in each species, and only 25.6, 19 and 16.4% of the initial concentration remained in the perfusate at the end (60 min) of the experiment in Fischer 344, Sprague-Dawley rats and rabbits, respectively. No metabolism of A was detected by the high-performance liquid chromatography technique. Raising the initial concentration of A from 0.3 to 120 microM (n = 26) in the Fischer 344 rats apparently did not saturate the uptake process, and the tissue/medium ratio averaged 122.5. The uptake of desethylamiodarone (DEA), the main metabolite of A in vivo, was more extensive (tissue/medium ratio = 506) than that of the parent compound. DEA also was not metabolized by the isolated perfused lungs. Lung homogenate incubations fortified with cofactors did not metabolize A or DEA. We conclude that in the isolated perfused lungs: A is extensively taken up by the lungs of rats and rabbits; the uptake is not saturated by raising the concentrations over a 400-fold range; DEA is taken up more readily than A; and metabolism of neither compound is observed.

Topics: Amiodarone; Animals; Benzofurans; Chromatography, High Pressure Liquid; In Vitro Techniques; Lipidoses; Lung; Male; Perfusion; Phospholipids; Rabbits; Rats; Rats, Inbred F344; Rats, Inbred Strains

Amiodarone is a useful antiarrhythmic agent whose pharmacokinetics are incompletely characterised. In order to optimise efficacy of an antiarrhythmic drug, information regarding plasma concentrations achieved during use of the drug is necessary. We report plasma amiodarone and desethylamiodarone concentrations in eight patients following intravenous infusion at a rate of 175 mg h-1 for the first 2 h, followed by infusion at a rate of 50 mg h-1 for a further 46 h a regimen very similar to that recommended by the manufacturers. In at least three of eight patients plasma concentrations were below the suggested therapeutic range of 1.0-2.5 mg l-1 from 3 to 16 h after the infusion was started. Our data suggests that larger doses of intravenous amiodarone than those previously recommended may be necessary to obtain optimal benefit from the drug.

Topics: Aged; Amiodarone; Benzofurans; Female; Heart Diseases; Humans; Infusions, Parenteral; Kinetics; Male; Middle Aged

Amiodarone is a potent class III antiarrhythmic agent that has a slow onset of action in patients (ca. 20 days). To determine if myocardial accumulation of desethylamiodarone (DEA), its main metabolite, influences its antiarrhythmic activity, three groups of six Wistar rats were given amiodarone, 50 mg/kg/day i.p. (A groups), and three groups received the same dose of amiodarone in combination with 80 mg/kg/day of phenobarbital to induce hepatic biotransformation (AP groups). After 3, 7 or 21 days, the rats were sacrificed and the ventricular effective refractory period (VERP) was determined by the extrastimulus technique in endocardial preparations superfused in the tissue bath. Control measurements of VERP were done in untreated rats. Myocardial concentrations of DEA measured by high-performance liquid chromatography were significantly higher in the AP groups than in the A groups (7.5 +/- 0.83 vs. 2.27 +/- 0.11 micrograms/g at 3 days, 6.09 +/- 0.70 vs. 2.82 +/- 0.30 micrograms/g at 7 days and 11.93 +/- 1.22 vs. 4.79 +/- 1.84 micrograms/g at 21 days: mean +/- S.E.). Control VERP value was 33.4 +/- 1.2 msec and was increased by 9, 35 and 42% after 3, 7 and 21 days in the A groups, and by 9, 38 and 39% in the AP groups. After 7 days of DEA administration yielding myocardial concentrations similar to those obtained after amiodarone treatment, there was a slight but nonsignificant prolongation of the VERP (12%). Thus, the prolongation of VERP after amiodarone administration did not appear to depend on myocardial DEA accumulation, suggesting that the slow onset of amiodarone class III action may not be related to DEA disposition.

Topics: Action Potentials; Amiodarone; Animals; Benzofurans; Biotransformation; Heart Ventricles; Kinetics; Male; Myocardium; Phenobarbital; Rats; Rats, Inbred Strains; Time Factors

Administration of amiodarone hydrochloride (50-150 mg/kg i.p. daily) to rats, mice or hamsters resulted in the in vivo formation of a cytochrome P-450Fe(II)-amiodarone metabolite complex absorbing at 453 nm, unable to bind CO and biologically inactive. In rats, the amount of complex present in hepatic microsomes was small 24 hr after administration of a single dose of amiodarone (100 mg/kg i.p.) but was increased 2.5-times by pretreatment with phenobarbital and 8-times by pretreatment with dexamethasone phosphate. In addition, the complex increased linearly with time as the doses of amiodarone were repeated daily. When both enhancing factors were combined (treatment for 3 days with both dexamethasone and amiodarone), the amount of complex present in liver microsomes reached 0.78 nmol/mg protein or 40% of total cytochrome P-450 in rats. In these rats, in vitro disruption of the complex with potassium ferricyanide suppressed its Soret peak at 453 nm, increased by 70% the CO-binding spectrum of dithionite-reduced microsomes, and restored several monooxygenase activities. The 453 nm-absorbing complex was also formed in vitro upon incubation of amiodarone or N-desethylamiodarone with NADPH, EDTA and microsomes from dexamethasone-treated rats. The formation of the complex was smaller with microsomes from phenobarbital-treated rats and was not detected with microsomes from control rats. We conclude that amiodarone forms an inactive cytochrome P-450Fe(II)-metabolite complex in rats, mice and hamsters.

Topics: Amiodarone; Animals; Benzofurans; Carbon Monoxide; Cricetinae; Cytochrome P-450 Enzyme System; Dexamethasone; Dithionite; Dose-Response Relationship, Drug; Ferrous Compounds; Iron; Liver; Male; Mice; Organ Size; Oxygenases; Rats; Rats, Inbred Strains; Time Factors

The effect of acute administration of amiodarone, its major metabolite desethylamiodarone and iodine in an amount equal to that contained in amiodarone on serum thyroid hormone and thyrotropin (TSH) concentrations and hepatic and pituitary 5' deiodination of thyroxine (T4) in the euthyroid and hypothyroid rat was evaluated. Amiodarone, desethylamiodarone and iodine all caused a decrease in serum T4 and triiodothyronine (T3) concentrations in euthyroid rats, while serum TSH concentrations and pituitary and hepatic 5' deiodinase activities were decreased only in the amiodarone and desethylamiodarone-treated animals. Serum TSH was increased in the iodine treated rats. Amiodarone, but not iodine, decreased serum T3 and TSH concentrations and pituitary and hepatic 5' deiodinase activities in hypothyroid rats. Inhibition of hepatic 5' deiodinase activity was also observed by the addition of amiodarone in vitro in the absence of dithiothreitol (DTT) but not in the presence of DTT. The decrease in the serum T4 concentration observed with amiodarone and desethylamiodarone administration is probably secondary to the inhibitory effect of iodine released from the drugs on thyroidal T4 synthesis and secretion. Iodine inhibition of thyroidal T3 synthesis and secretion, decreased T4 substrate for a peripheral generation of T3 and inhibition of T4 to T3 conversion all contribute to the decrease in serum T3 observed. The decrease in the serum TSH concentration, despite low serum T4 and T3 concentrations and inhibition of pituitary 5' deiodinase, suggest that amiodarone may function as a thyroid hormone agonist in the pituitary.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amiodarone; Animals; Benzofurans; Hypothyroidism; In Vitro Techniques; Iodide Peroxidase; Liver; Male; Pituitary Gland; Rats; Rats, Inbred Strains; Thyroid Hormones; Thyrotropin

In eight patients, the right ventricular effective refractory period, rate-dependent changes in intraventricular conduction (as reflected by QRS duration during ventricular paced cycle lengths of 600 to 250 ms) and results of programmed ventricular stimulation were determined in the control state, 5 minutes after the intravenous infusion of 10 mg/kg body weight of amiodarone and after 2 months of treatment with oral amiodarone. The right ventricular effective refractory period was 230 +/- 30 ms (mean +/- SD) in the control study, 248 +/- 27 ms after intravenous amiodarone (p less than 0.001) and 296 +/- 26 ms after oral amiodarone (p less than 0.001). In the control state, QRS duration was constant at all paced cycle lengths. Intravenous amiodarone resulted in a rate-dependent prolongation of QRS duration. This rate-dependent prolongation was markedly accentuated by oral amiodarone in six patients who had an elevated serum level of reverse triiodothyronine (T3) after 2 months of oral treatment, but it was not more pronounced than the effects of intravenous amiodarone in two patients with a normal reverse T3 serum level after oral therapy. Both intravenous and oral amiodarone either suppressed or modified the induction of ventricular tachycardia by programmed stimulation in some patients, but in a discordant fashion. The relative effects of intravenous and oral amiodarone on ventricular refractoriness and conduction and on ventricular tachycardia induction did not correlate with serum amiodarone levels. Chronic amiodarone therapy results in a marked prolongation in ventricular refractoriness compared with the relatively small but significant increase that occurs after intravenous amiodarone.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Aged; Amiodarone; Benzofurans; Cardiac Pacing, Artificial; Electric Stimulation; Electrophysiology; Female; Heart Conduction System; Heart Ventricles; Humans; Infusions, Parenteral; Male; Middle Aged; Tachycardia; Time Factors; Triiodothyronine

Iodine kinetic studies were performed serially in 15 patients taking 300 mg amiodarone/day for 6 months to assess the biological significance of the high iodine content of the drug. Urinary inorganic iodide excretion increased from 0.25 +/- 0.03 (+/- SE) mumol/mmol creatinine before treatment to over 7 mumol/mmol during therapy. Thyroid iodide clearance fell from 5.93 +/- 0.82 ml/min to less than 0.5 ml/min, while plasma inorganic iodide rose from 0.05 +/- 0.01 mumol/liter to approximately 2.2 mumol/liter during treatment. Thyroid absolute iodide uptake rose from 16.3 +/- 2.7 to 54.6 +/- 5.7 nmol/h after 6 weeks of therapy (P less than 0.001). Thereafter, it progressively declined, but it was still significantly elevated (32.0 +/- 4.3 nmol/h) after 24 weeks (P less than 0.01). The calculated daily excretion of inorganic iodide rose to over 80 mumol during the study, accounting for about 10% of amiodarone iodine. During this time, the patients all had the characteristic plasma thyroid hormone changes associated with amiodarone therapy, i.e. increased T4, free T4, and rT3 and decreased T3, while remaining clinically euthyroid. The massive increase in available inorganic iodide during amiodarone treatment is probably responsible for the induction of both the hypothyroidism and the thyrotoxicosis that can occur in patients receiving the drug.

Topics: Adult; Aged; Amiodarone; Benzofurans; Biological Availability; Female; Humans; Iodides; Iodine; Kinetics; Male; Mathematics; Metabolic Clearance Rate; Middle Aged; Thyroid Gland; Thyroid Hormones

Desethylamiodarone is the principal metabolite of amiodarone. Amiodarone is a class III antiarrhythmic agent, which acts by lengthening repolarization in the myocardium, an effect that is identical to that produced by hypothyroidism. Amiodarone is known to alter thyroid hormone metabolism, and it has been suggested that the mechanism underlying its antiarrhythmic action is the induction of a myocardial but not generalized hypothyroidism. Since the serum levels of desethylamiodarone reach those of the parent compound during chronic amiodarone therapy, it has been suggested that at least part of amiodarone's pharmacological effects may be attributable to the additive effects of the metabolite. Therefore, we investigated the effects of desethylamiodarone on thyroid hormone metabolism and compared them with those of amiodarone in rats. We have shown that chronic treatment with desethylamiodarone decreased serum T3, markedly increased serum reverse T3 with no significant change in serum T4. These effects are similar to those of amiodarone. The data suggest that the chronic effects of amiodarone on thyroid hormone metabolism may be due at least in part to the actions of desethylamiodarone.

Topics: Amiodarone; Animals; Benzofurans; Chemical Phenomena; Chemistry; Male; Rats; Rats, Inbred F344; Thyroid Hormones; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

The interrelationships between serum levels of amiodarone, desethylamiodarone, and reverse T3, and changes in the corrected QT interval (delta QTc) were examined in 22 patients during long-term treatment with amiodarone. At 1, 3, and 6 months of follow-up, the correlation coefficient between serum levels of amiodarone or desethylamiodarone and reverse T3 ranged from 0.01 to -0.2 (p greater than 0.4). At the same time intervals, the correlation coefficient between both amiodarone and desethylamiodarone levels and delta QTc ranged from 0.1 to -0.1 (p greater than 0.6), and the correlation coefficient between reverse T3 and delta QTc also ranged between 0.1 to -0.1 (p greater than 0.5). Substituting percent delta QTc for delta QTc also did not reveal a significant correlation. These data demonstrate that serum levels of reverse T3 cannot be used as a substitute for serum levels of amiodarone in monitoring patients being treated with amiodarone. The absence of a correlation between serum reverse T3 levels and delta QTc suggests that the delay in repolarization which occurs during amiodarone therapy is not secondary to an amiodarone-induced abnormality in thyroid hormone metabolism.

Topics: Adult; Aged; Amiodarone; Arrhythmias, Cardiac; Benzofurans; Electrocardiography; Female; Follow-Up Studies; Humans; Male; Middle Aged; Time Factors; Triiodothyronine, Reverse

Amiodarone and its major metabolite, desethylamiodarone, were measured in the plasma, white blood cells (WBCs) and red blood cells (RBCs) of 14 patients receiving chronic amiodarone therapy. The mean plasma concentrations (+/- standard error of the mean) of amiodarone and desethylamiodarone were 2.4 +/- 0.6 and 1.6 +/- 0.4 microgram/ml, respectively. The drug level in the WBCs was 62 +/- 12 micrograms/g protein during the early loading phase and 106 +/- 33 micrograms/g protein during maintenance phase of amiodarone therapy. Desethylamiodarone concentration in the WBCs was 42 +/- 18 and 190 +/- 33 micrograms/g protein during the loading and maintenance phases, respectively. Although a trend in WBC to plasma concentration was seen, there was no linear correlation between these levels. In 1 patient with severe neuropathy, biopsy of the nerve and muscle showed high concentrations of both amiodarone and desethylamiodarone. Although there was a decrease in tissue drug levels, proportionately high tissue:plasma drug levels were detected at the time of necropsy approximately 6.5 months after amiodarone was discontinued in this patient. Neutrophils from all patients receiving chronic amiodarone therapy showed multiple myelin-like polymorphic inclusion bodies (onionoid bodies) upon electron microscopic examination. Our observations suggest that WBC drug concentrations and electron microscopic changes may provide a means of correlating tissue concentrations and of following patients receiving chronic amiodarone therapy.

Topics: Amiodarone; Benzofurans; Chromatography, High Pressure Liquid; Erythrocyte Count; Female; Half-Life; Humans; Leukocyte Count; Male; Microscopy, Electron; Neutrophils; Time Factors

Topics: Amiodarone; Benzofurans; Chromatography, High Pressure Liquid; Humans; Indicators and Reagents; Tears; Trifluoperazine

Phenobarbitone pretreatment has been shown to increase amiodarone total clearance and decrease amiodarone elimination half-life after a single intravenous amiodarone dose in the rat. Coadministration of phenobarbitone with amiodarone for 7 days resulted in decreased tissue amiodarone levels compared to controls. These results may have implications for patients undergoing therapy with amiodarone and concomitant potent enzyme inducing drugs.

Topics: Amiodarone; Animals; Benzofurans; Kinetics; Male; Phenobarbital; Rats; Rats, Inbred Strains

Three patients developed peripheral neuropathy after taking amiodarone for more than 18 months. All had high serum concentrations of amiodarone and its desethyl metabolite; in one patient concentrations in a sural nerve biopsy were 80 times higher than in serum. Peripheral neuropathy is a complication of large doses of amiodarone taken over long periods.

Topics: Aged; Amiodarone; Benzofurans; Female; Humans; Male; Middle Aged; Peripheral Nervous System Diseases

A single bolus of 5 or 40 mg/Kg of amiodarone was injected 24 hours after inducing coronary artery occlusion in the closed-chest dog preparation. Plasma pharmacokinetic profile was determined and the calculated t1/2 beta of 3.5 +/- 2.8 and 3.2 +/- 0.6 hour after 5 or 40 mg/Kg dose, respectively, were obtained. The major metabolite, desethylamiodarone, was detected within 15 minutes of the single bolus of amiodarone. At 6 hours after amiodarone administration, the animals were killed and tissue concentrations of amiodarone and desethylamiodarone were measured. Two additional peaks in the HPLC chromatograms were observed in plasma and tissue samples of most dogs given 40 mg/Kg I.V. amiodarone and these most likely are due to unidentified metabolites of the drug. The highest drug concentration was found in the lungs. Tissue to plasma drug rations suggested that accumulation of amiodarone and perhaps desethylamiodarone was different for different tissues. Ventricular arrhythmias were not abolished by either of the two doses of amiodarone; however, there was a gradual and statistically significant decrease in the number of ventricular premature beats and ventricular tachycardia beats over the six-hour period after a single 40 mg/Kg I.V. bolus. At the time of reduction in the arrhythmia frequency, tissue levels of both amiodarone and desethylamiodarone in the border and infarct zone of the myocardium were approximately 50% as high as in the normal zone. Plasma drug levels did not correlate well with tissue concentrations. However, there was an excellent correlation between drug levels in WBCs and various tissues except the lung. It is concluded that amiodarone is rapidly metabolized into desethylamiodarone and at least two other unidentified compounds; a large dose of amiodarone is necessary to produce some decrease in ventricular arrhythmias associated with acute coronary artery occlusion; tissue concentrations may be better correlated with drug levels in WBCs than in plasma, and coronary artery occlusion does not affect acute pharmacokinetic profile of the drug.

Topics: Amiodarone; Animals; Arrhythmias, Cardiac; Benzofurans; Biotransformation; Chromatography, High Pressure Liquid; Dogs; Dose-Response Relationship, Drug; Electrocardiography; Female; Heart Conduction System; Hemodynamics; Male; Myocardial Infarction; Myocardium

This study demonstrated the rapid antiarrhythmic effects of oral amiodarone (Am). A single 30 mg/kg dose was given to 67 patients, 18 with supraventricular arrhythmias (atrial extrasystoles: 11 cases, reciprocating tachycardia: 4 cases, intraatrial reentrant tachycardia: 2 cases, paroxysmal atrial fibrillation, AF: 1 case). Eighteen patients had permanent AF. Thirty-one patients had ventricular arrhythmias (ventricular extrasystoles, VES, isolated or in salvos: 22 cases, and ventricular tachycardia, VT: 19 cases). The effect on atrial extrasystoles was significant 4 to 13 hours after AM and maximal (-98% +/- 3.6%) at 7.7 +/- 1 hours. They recurred in 3 cases at the 18th hour. No significant effects were observed on the other supraventricular tachycardias. The effect on the atrioventricular node (AVN) assessed by the ventricular response to permanent AF, was significant after the 3rd hour and maximal ( = 38 +/- 6 bpm) at the 7th hour. The reduction in the frequency of VES was significant from the 5th to the 19th hour of treatment. Control of VT was obtained in 5 cases between the 3rd and 8th hours. The treatment was well tolerated as no side effects were reported. The plasma concentration (PC) of amiodarone (54 patients) and of N-desethylamiodarone (NDA) (36 patients) were measured; the maximal values were 2.53 +/- 1.5 mg/l for Am and 0.22 +/- 0.1 mg/l for NDA. A 60% decrease in the number of VES was observed with PC of Am of 1.90 +/- 0.3 mg/l and a 20% reduction in the ventricular response to AF at PC of Am of 1.50 +/- 0.33 mg/l.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Amiodarone; Arrhythmias, Cardiac; Benzofurans; Dose-Response Relationship, Drug; Female; Humans; Kinetics; Male

The pharmacokinetic characteristics of amiodarone suggest extensive tissue deposition. We confirmed this by measuring tissue concentrations of the drug and of its major metabolite, desethylamiodarone, in human tissues. These were obtained at autopsy (n = 9), surgery (n = 7), or biopsy (n = 2) from 18 patients who had been treated with amiodarone for varying periods of time. High concentrations of amiodarone were found in fat (316 mg/kg wet weight in autopsy specimens, 344 mg/kg wet weight in biopsy specimens). Amiodarone and desethylamiodarone concentrations (mg/kg wet weight, autopsy samples) were also high in liver (391 and 2354), lung (198 and 952), adrenal gland (137 and 437), testis (89 and 470), and lymph node (83 and 316). We also found high concentrations of amiodarone (306 mg/kg wet weight) and desethylamiodarone (943 mg/kg wet weight) in abnormally pigmented ("blue") skin from patients with amiodarone-induced skin pigmentation. These values were 10-fold higher than those in unpigmented skin from the same patients. These high concentrations were associated with lysosomal inclusion bodies in dermal macrophages in the pigmented skin. The inclusion bodies were intrinsically electron dense and were shown to contain iodine by energy dispersive x-ray microanalysis. Lysosomal inclusion bodies shown by electron microscopy to be multilamellar were seen in other tissues. These tissues included terminal nerve fibers in pigmented skin, pulmonary macrophages, blood neutrophils, and hepatocytes and Kupffer cells. These characteristic ultrastructural findings occur in both genetic lipidoses and lipidoses induced by other drugs, e.g., perhexiline. We conclude that during therapy with amiodarone, widespread deposition of amiodarone and desethylamiodarone occurs. This leads to ultrastructural changes typical of a lipidosis. These changes are seen clearly in tissues associated with the unwanted effects of amiodarone, e.g., skin, liver and lung.

Topics: Adolescent; Adult; Aged; Amiodarone; Arrhythmias, Cardiac; Benzofurans; Coronary Disease; Female; Humans; Liver; Long-Term Care; Lung; Male; Middle Aged; Skin

The relative and absolute bioavailability of different oral forms of amiodarone was examined in 12 subjects. The doses were 5 mg/kg iv, two 200-mg commercial tablets by mouth, two 200-mg tablets (new formulation) by mouth, and 400 mg in a drinkable solution. Plasma levels of amiodarone and its N-desethylated metabolite were determined by HPLC. Statistical analysis indicated bioequivalence of the oral forms for all the kinetic parameters examined. After oral dosing, amiodarone was slowly absorbed and the maximum plasma level (0.55 +/- 0.20 mg/l) was reached in 4.5 hr. The absolute bioavailability of oral amiodarone was calculated by comparison of AUCs after oral dosing with those after intravenous injection. A mean oral bioavailability of 65% +/- 22% was indicated. Since the tablets were bioequivalent to the drinkable solution, incomplete absorption seems not be a result of the dissolution characteristics of the commercial formulation but rather of a first-pass effect.

Topics: Administration, Oral; Adult; Amiodarone; Benzofurans; Biological Availability; Chromatography, High Pressure Liquid; Female; Humans; Injections, Intravenous; Male; Random Allocation; Tablets; Time Factors

In 65 patients a single oral dose of amiodarone (30 mg/kg) produced an antiarrhythmic effect on supraventricular or ventricular arrhythmias within 3 to 8 hours and lasted for 17 to 19 hours. On the second day a 15-mg/kg dose reproduced this effect within 3 to 9 hours. Plasma concentration of amiodarone increased to a maximum (2.2 +/- 1.7 mg/liter) mean +/- standard deviation) at 6 +/- 3.5 hours and plasma levels of N-desethylamiodarone (NDA) rose to 0.2 +/- 0.08 mg/liter at 12 +/- 6.4 hours. Sixty-one other patients were given a single 30-mg/kg dose 7 hours to 4 days before open heart surgery. Biopsies of the right atrial and left ventricular walls were taken during surgery. Myocardial concentration of amiodarone was maximal in the atrium after 7 hours (13 +/- 8 mg/kg) and in the ventricle after 24 hours (17 +/- 11 mg/kg). NDA myocardial concentration increased progressively until 24 hours and then remained stable over 4 days (1.5 mg/kg). The amiodarone myocardial to plasma concentration ratio was similar in the atrium and in the ventricle and averaged 22 and 10 for amiodarone and NDA, respectively. A significant relation existed between amiodarone concentration and the effect on ventricular premature complexes (r = 0.74, p less than 0.001) and between amiodarone plasma concentration and the effect on the atrioventricular conduction (r = 0.58, p less than 0.001). The plasma concentration of amiodarone corresponding to a 60% decrease in arrhythmias averaged 1.5 to 2 mg/liter.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Adult; Aged; Amiodarone; Arrhythmias, Cardiac; Atrial Fibrillation; Atrioventricular Node; Benzofurans; Dose-Response Relationship, Drug; Electrocardiography; Female; Heart Atria; Humans; Male; Middle Aged; Myocardium; Tachycardia; Time Factors

Two cases are reported in which amiodarone was administered during pregnancy for longer periods than has been reported previously. Limited placental transfer of amiodarone and its desethyl metabolite was observed in both cases. A normal child resulted from each pregnancy despite, in one case, amiodarone therapy throughout the entire pregnancy. However, caution is urged in the use of amiodarone during pregnancy in view of the limited data available.

Topics: Adult; Amiodarone; Arrhythmias, Cardiac; Benzofurans; Female; Humans; Maternal-Fetal Exchange; Pregnancy; Pregnancy Complications, Cardiovascular

A rapid high-performance liquid chromatographic assay was developed for the determination of amiodarone (1) and its N-deethyl metabolite (desethylamiodarone, 2) in plasma, urine, and bile. Analysis was performed on a C18 reversed-phase column and precolumn using a mobile phase consisting of methanol:water:58% ammonium hydroxide (94:4:2) delivered at a flow rate of 1.5 mL/min. The eluant was monitored at 244 nm. Under these conditions, 1, 2, and the internal standard eluted with retention times of 5.5, 4.6, and 6.8 min, respectively. Samples (100 microL) of plasma were prepared by precipitating the plasma proteins with acetonitrile containing the internal standard and injecting an aliquot of the supernatant directly onto the column. Samples (100 microL) of urine and bile were prepared for injection by acidifying the sample with concentrated HCl and then extracting the mixture with six volumes of 2,2-dimethoxyproprane. The recovery of 1 and 2 from plasma was virtually complete. The recovery from urine and bile was 80-90% for 1 and 60-65% for 2. The limit of sensitivity of both compounds in plasma was 100 ng/mL. For urine and bile, the detection limits were 1 and 5 micrograms/mL, respectively. Over the plasma concentration range of 0.1-10.0 micrograms/mL, the within-day CV ranged from 1 to 10% for 1 and from 1 to 8% for 2. The between-day CV ranged from 2 to 12% and from 1 to 17% for 1 and 2, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amiodarone; Animals; Benzofurans; Bile; Chromatography, High Pressure Liquid; Drug Stability; Humans; Kinetics; Male; Rats; Rats, Inbred Strains

Tissue distribution of amiodarone (Cordarone) and desethylamiodarone in the rat was studied after repeated intraperitoneal administration of the drug. Tissue and serum concentrations of amiodarone and desethylamiodarone were determined by high-performance liquid chromatography. The levels of amiodarone and desethylamiodarone in serum and tissues obtained after repeated intraperitoneal application of doses varying from 25 mg to 200 mg/kg show that the accumulation of amiodarone and desethylamiodarone in the rat is dose-dependent and both drugs are preferentially distributed in decreasing order in adipose tissue, lung, liver, kidney and thyroid gland. The penetration of the drug and its metabolite into brain was poor and with all the applied dosages brain levels were considerably lower than the corresponding serum levels. Desethylamiodarone serum and tissue concentrations were substantially lower than the corresponding amiodarone concentrations and varied from 1 to 48% (mean 15%) depending on the dosage used and the kind of tissue. The amiodarone tissue/serum concentration ratios were exceptionally high in adipose tissue (1,000-4,000) and moderate to high in the other tissues except brain (5-90), and indicate an extensive distribution of the drug with fat as a reservoir with a large storage capacity. The levels of amiodarone and desethylamiodarone, obtained with 50 mg/kg and 100 mg/kg dosages, showed in function of time clearly an increase in serum and tissues. The observed amiodarone tissue/serum ratios in function of time revealed no further significant increase (p less than or equal to 0.05) after 3 injections over a 6-day period, indicating the attainment of "steady-state".(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amiodarone; Animals; Benzofurans; Chromatography, High Pressure Liquid; Injections, Intraperitoneal; Male; Rats; Rats, Inbred Strains; Time Factors; Tissue Distribution

In eight patients who had previously responded to treatment with oral amiodarone for prevention of recurrent supraventricular paroxysmal tachycardia, a new regimen of oral amiodarone dosing was evaluated. Each patient received the entire dose, previously taken throughout one week (600 to 1,200 mg), on a single day, once each week. After six weeks on this regimen, all patients were still free of arrhythmias and there were no adverse reactions to the drug. In the first week of the new treatment, amiodarone plasma levels gradually fell from 1.83 mg/l, to 0.48 mg/l, on average. The trough level was similar to that obtained when the drug was given on a daily basis. It is concluded that this new regimen can be used for patients receiving oral amiodarone, and it may be advantageous in improving the compliance of some patients.

Topics: Amiodarone; Benzofurans; Female; Humans; Kinetics; Male; Tachycardia, Paroxysmal

Amiodarone is an effective antiarrhythmic agent whose use is associated with several drug interactions one of which is potentiation of the action of warfarin. The mechanism of this interaction has hitherto been unclear. We examined possible mechanisms in eight patients. Total plasma warfarin clearance was found to be reduced by amiodarone. No change was detected in the binding of warfarin to plasma proteins. No relationship was found between plasma amiodarone concentrations and the change in warfarin clearance.

Topics: Aged; Amiodarone; Benzofurans; Blood Proteins; Female; Humans; Male; Middle Aged; Protein Binding; Warfarin

In 23 patients treated with the iodine-containing antiarrhythmic drug amiodarone, the plasma concentrations of amiodarone, desethylamiodarone and iodine have been studied. Besides amiodarone and desethylamiodarone, a pool of iodine-containing substances, NANDAI (non-amiodarone-, non-desethylamiodarone-iodine), was present. At steady state the iodine content of NANDAI amounted to 64% and the iodine content of amiodarone plus desethylamiodarone to 36% of total serum iodine. At steady state 26% of the NANDAI fraction was made up of inorganic iodide, the average plasma concentration of which was at least 40 times above the upper limit of the normal range. The serum elimination half-life of NANDAI of 57-160 days exceeded that of amiodarone (35-68 days) and of desethylamiodarone (31-110 days). At steady state the serum concentration of desethylamiodarone appears to be related to the concentration of amiodarone by a Michaelis-Menten type function, yielding a Km of amiodarone of 2.45 mumol/l and a maximal desethylamiodarone concentration of 3.61 mumol/l.

Topics: Adolescent; Adult; Aged; Amiodarone; Angina Pectoris; Arrhythmias, Cardiac; Benzofurans; Female; Half-Life; Humans; Iodides; Iodine; Kinetics; Male; Middle Aged; Time Factors

Tissue distribution of amiodarone (Cordarone) and desethylamiodarone in the rat was investigated after repeated oral application of various dosages of the drug. Serum and tissue concentrations ofBamiodarone and desethylamiodarone were assessed by high-performance liquid chromatography. The amiodarone and desethylamiodarBne serum and tissue levels obtained after repeated oral application of doses ranging from 25 to 100 mg/kg reveal that the accumulation of amiodarone and desethylamiodarone in the rat is dose-dependent. Amiodarone is preferentially distributed in decreasing order in adipose tissue, lung, thyroid gland, kidney and liver whereas its metabolite shows the highest affinity for lung then followed by kidney, thyroid gland, adipose tissue and liver. The penetration of amiodarone and desethylamiodarone into brain was poor and with all the applied dosages brain levels were in the same range as the corresponding serum levels. Desethylamiodarone serum and tissue concentrations were consistently lower than the corresponding amiodarone concentrations and varied from 5 to 78% (mean 45%) depending on the dose administered and the kind of tissue. The amiodarone tissue/serum concentration ratios were very high in adipose tissue (220-340) and moderate to high in the other tissues except brain (3-100) and indicate an extensive distribution of the drug with fat as a depot with a large storage capacity. The desethylamiodarone tissue/serum concentration ratios were very high in lung tissue (50-620), high in renal, thyroid and adipose tissue (20-390) and moderate in the other tissues except brain (3-90), respectively, and indicate an extensive distribution of the metabolite with fat as a reservoir and lung, kidney and thyroid gland, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Amiodarone; Animals; Benzofurans; Biotransformation; Chromatography, High Pressure Liquid; Male; Rats; Tissue Distribution

Topics: Amiodarone; Benzofurans; Half-Life; Humans; Male; Middle Aged; Peripheral Nervous System Diseases; Tachycardia

An antiarrhythmic treatment was done in 56 patients with recurrent ventricular tachycardias using amiodarone. The dosage was 400 to 600 mg/d following a loading dosage of 1000 mg for 8 to 12 days. Amiodarone and desethylamiodarone concentration in serum (control group n = 33) and in erythrocyte haemolysate (control group n = 13) were determined in relapses of ventricular tachycardias (n = 7) and in pulmonary fibrosis as serious side effect (n = 3). It was shown that amiodarone levels rise continuously during loading treatment until the 8th to 12th day and that desethylamiodarone can be demonstrated after the 3rd day of treatment. The mean concentrations (+/- standard deviation) of amiodarone and desethylamiodarone were 2.21 +/- 0.89 microgram/ml and 1.3 +/- 0.74 microgram/ml in serum and 0.97 +/- 0.65 microgram/ml and 1.95 +/- 1.9 micrograms/ml in erythrocyte haemolysate. Amiodarone levels did not correlate with efficacy and with incidence of side effects. However, in pulmonary fibrosis high desethylamiodarone concentrations in serum (greater than 2.5 micrograms/ml) and in erythrocyte haemolysate (greater than 4 micrograms/ml) were found. Four out of 7 patients with recurrent ventricular tachycardia showed relatively low desethylamiodarone concentrations in serum (desethylamiodarone/amiodarone ratio less than 0.4). Thus control of amiodarone treatment can be enlarged by determination of desethylamiodarone levels as its concentrations correlate with relapses of ventricular tachycardias and serious side effects.

Topics: Adult; Aged; Amiodarone; Arrhythmias, Cardiac; Benzofurans; Erythrocytes; Humans; Long-Term Care; Middle Aged; Pulmonary Fibrosis

The relationship of apparent steady-state serum concentrations of amiodarone and its metabolite, desethylamiodarone, to therapeutic and toxic effects was assessed in 127 patients who had treatment-resistant ventricular or supraventricular arrhythmias or were intolerant to other agents. After at least 2 months (mean, 9.8) of treatment with daily maintenance doses of 200 to 600 mg, arrhythmias were effectively suppressed in 78% of patients. Arrhythmias recurred in 47% of patients with serum amiodarone concentrations of less than 1.0 mg/L, whereas only 14% of patients with higher concentrations had recurrences (p less than 0.005). Side effects, most of them mild, occurred in 57%; only 9 patients required discontinuation of drug therapy. The risk of developing adverse reactions was related to serum amiodarone concentrations (p less than 0.0001). Adverse reactions were common in patients with serum values exceeding 2.5 mg/L, although pulmonary complications did occur at lower concentrations. Monitoring serum amiodarone concentrations may differentiate failure of drug therapy from suboptimal dosing and reduce the incidence of concentration-related side effects.

Topics: Adult; Aged; Amiodarone; Arrhythmias, Cardiac; Benzofurans; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Male; Middle Aged; Recurrence; Tachycardia; Ventricular Fibrillation

The serum kinetics of amiodarone and its major metabolite the deethyl analogue were studied in rabbits after intravenous administration. The elimination of the drug and the metabolite from serum occurred as a biexponential function. Both compounds exhibited a rapid distribution phase (6.5 and 4.4 min, respectively) and had elimination half-lives of 136 and 235 min, respectively. There was a rapid uptake of both drugs by the myocardium, with maximal concentrations at 5 and 15 min. The myocardial concentrations were higher than the respective serum concentrations and declined with time. There was a wide scatter in myocardium-serum ratios, which ranged from 1 to 11 for amiodarone and 12 to 29 for the metabolite. Neither the drug nor the metabolite produced significant changes in the surface electrocardiogram after intravenous administration. These data suggest that accumulation of the metabolite does not account for the slow onset of action of amiodarone.

Topics: Amiodarone; Animals; Benzofurans; Electrocardiography; Female; Injections, Intravenous; Kinetics; Myocardium; Rabbits

The hepatic extraction of amiodarone and N-desethylamiodarone has been investigated in seven patients following catheterization of the portal and hepatic veins under general anaesthesia. Amiodarone (600 mg) was administered orally 4 h before regional blood sampling. Concentrations of amiodarone and N-desethylamiodarone, determined by h.p.l.c., were about twice as high in the portal vein compared with those in the hepatic vein, the calculated hepatic extraction ratios of both compounds being 0.39 +/- 0.07 and 0.34 +/- 0.03, respectively. The presence of N-desethylamiodarone in the portal vein in higher concentrations than in the hepatic vein strongly suggests that N-dealkylation of amiodarone occurs in the gut wall or lumen, a finding which might account for the low and highly variable intersubject amiodarone bioavailability.

Topics: Administration, Oral; Adult; Amiodarone; Benzofurans; Female; Humans; Liver; Male

The increasing use of amiodarone as antiarrhythmic drug has raised the possibilities of dangerous effects from amiodarone-digitalis interaction. We have studied twelve patients who were taking digitalis and to whom amiodarone was administered because of arrhythmias. We found a 75,42% increase of digitalis plasma levels (p less than 0,001) in the early days of amiodarone therapy, and a 52,1% increase (p less than 0,001) in the medium term. An inverse correlation was found (r = -0,65; p less than 0,05) between the plasma levels of digitalis during the steady-state control period and during the following 2-to-6 months evaluation. Acute episodes of cardiac failure caused in our patients an abrupt increase of digitalis plasma levels: in three patients digitalis toxicity occurred. Based on our experience, we recommend that the dose of digitalis be halved when the two drugs are given together in patients with various degree of cardiac failure; moreover digitalis plasma levels should be frequently monitored in these patients. On the other hand digitalis administered according to age, sex, weight, kidney function, together with amiodarone, can be given at full dosage in patients without cardiac failure.

Topics: Adult; Aged; Amiodarone; Arrhythmias, Cardiac; Benzofurans; Digitalis Glycosides; Digoxin; Drug Interactions; Female; Heart Diseases; Humans; Male; Medigoxin; Middle Aged

Amiodarone and a metabolite, desethylamiodarone, were measured in plasma of 55 patients and in both plasma and red blood cell (RBC) in 28 patients who received chronic amiodarone treatment. The assay for amiodarone and desethylamiodarone was performed by high-pressure liquid chromatography. During chronic treatment, median plasma concentration of amiodarone was 2.80 micrograms/ml and desethylamiodarone was 2.20 micrograms/ml. In matched samples, plasma amiodarone concentration exceeded RBC amiodarone concentration (p less than 0.001) and the RBC-to-plasma concentration ratio averaged 0.31. The plasma desethylamiodarone concentration was not significantly different from its RBC concentration, and the RBC-to-plasma concentration ratio averaged 1.29. There was a linear correlation between plasma concentrations of amiodarone and desethylamiodarone (r = 0.82) and between RBC concentrations of drug and metabolite (r = 0.71). Drug or metabolite concentrations in plasma and RBCs correlated directly with daily dosage of amiodarone. Adverse side effects during chronic amiodarone therapy were related most strongly to RBC drug and metabolite concentrations. The group with adverse side effects had a significantly higher RBC concentration of amiodarone, 150 vs 0.75 micrograms/ml (p less than 0.001), than did patients free of adverse effects. After dosage reduction, side effects abated and plasma and RBC concentrations of drug and metabolite decreased. These data indicate that there is an expected range of amiodarone and desethylamiodarone concentrations during chronic treatment and that adverse side effects correlate best with RBC concentrations of drug and metabolite. Red cell concentrations may reflect the amount of unbound, free amiodarone and desethylamiodarone in plasma.

Topics: Amiodarone; Anorexia; Benzofurans; Erectile Dysfunction; Erythrocytes; Humans; Male; Nausea; Saliva; Tachycardia; Ventricular Fibrillation

The concentrations of amiodarone (Cordarone) and desethylamiodarone in plasma after single oral and intravenous and long-term oral dosing were determined in seven normal subjects and 106 patients with various cardiac arrhythmias, respectively, using a high-performance liquid chromatographic method. The decline in amiodarone plasma concentration after a single intravenous 400 mg dose was described by a triexponential decay equation, with a mean terminal half-life (t1/2) of 34.5 h. Model independent parameters were calculated from the fits. Mean values for clearance and apparent volume of distribution were 14.7 +/- 7.2 l/h and 376 +/- 372 l. Following single oral doses of 400 mg, amiodarone plasma concentration time data were fitted in a triexponential function. The mean terminal half-life for amiodarone after oral dosage was 31.6 +/- 21.3 h. Amiodarone peak concentrations of 0.37 +/- 0.22 micrograms/ml were attained in 4.8 +/- 1.5 h. The bioavailability of oral amiodarone was only 31 +/- 26%, in part due to first-pass metabolism. Desethylamiodarone , the major metabolite of amiodarone, was present in plasma in very low levels of about 10 ng/ml in several volunteers after single intravenous or oral administration of amiodarone. The mean plasma amiodarone and desethylamiodarone levels in 106 patients, using a mean oral daily maintenance dosage of 440 +/- 253 mg for a mean period of 9.1 months, were 1.85 +/- 1.17 micrograms/ml and 1.35 +/- 0.71 micrograms/ml, respectively. The relationship between the steady state amiodarone and desethylamiodarone plasma concentrations and daily amiodarone maintenance dose in mg in 106 patients was investigated.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Adult; Aged; Amiodarone; Benzofurans; Biotransformation; Female; Humans; Injections, Intravenous; Kinetics; Male; Middle Aged; Tissue Distribution

A new method has been used to measure tissue levels of amiodarone and its major metabolite desethylamiodarone. Amiodarone-pigmented skin has a drug and metabolite concentration ten times that of non-pigmented skin. Iodine-rich amiodarone and its metabolite have been detected in secondary lysosomes by energy dispersive analysis of X-rays. Amiodarone induces a phototoxic reaction with an action spectrum in both the UV-B and UV-A wavelengths.

Topics: Adult; Amiodarone; Benzofurans; Chromatography, High Pressure Liquid; Electron Probe Microanalysis; Humans; Male; Microscopy, Electron; Middle Aged; Photosensitivity Disorders; Skin; Skin Pigmentation

Topics: Amiodarone; Benzofurans; Chromatography, Liquid; Humans

Topics: Amiodarone; Benzofurans; Chromatography, High Pressure Liquid; Humans; Reference Standards

The purpose of the present report is to review the available pharmacokinetic information on amiodarone with an emphasis on our own experience in monitoring serum amiodarone concentrations. We have found that 400 mg should be the maximal maintenance dose; if that treatment fails, careful addition of other antiarrhythmic agents is preferable over an increase in amiodarone dosage. Serum concentrations below 2.5 mg/L will significantly improve amiodarone's benefit-to-risk ratio.

Topics: Amiodarone; Animals; Benzofurans; Biological Availability; Cardiac Pacing, Artificial; Chromatography, High Pressure Liquid; Dogs; Half-Life; Humans; Kinetics; Rats; Tachycardia

A method is described for the measurement of amiodarone and desethylamiodarone in small tissue samples. With the exception of fat, for which lipase is used, the tissues are digested with a proteolytic enzyme. After the addition of an internal standard the analytes are extracted from the homogeneous digest into an organic solvent and measured by high-performance liquid chromatography (HPLC) with UV detection at 240 nm. The method shows good reproducibility using tissue samples as small as 20 mg and suggests extensive accumulation of both compounds in some tissues, with particularly high concentrations in tissues associated with adverse effects of the drug.

Topics: Adipose Tissue; Adult; Aged; Amiodarone; Animals; Benzofurans; Chromatography, High Pressure Liquid; Female; Humans; Lipase; Male; Methods; Middle Aged; Myocardium; Rabbits; Specimen Handling; Subtilisins; Tissue Distribution

The single-dose pharmacokinetics of amiodarone have been studied in volunteer subjects given 400 mg doses by the intravenous and oral routes. The data show the compound to have a very large volume of distribution, a low total clearance, and a long and variable terminal elimination half-life. In patients the terminal elimination half-life was on the order of 40 days, with a more rapid phase of elimination in the first few days following the withdrawal of therapy. The terminal elimination half-life of desethylamiodarone was longer than that of the parent compound. High concentrations of amiodarone and its desethyl metabolite were found in tissue samples, with fat forming a potentially large tissue reservoir of the drug.

Topics: Adipose Tissue; Adult; Aged; Amiodarone; Benzofurans; Female; Half-Life; Humans; Kinetics; Liver; Lung; Male; Metabolic Clearance Rate; Middle Aged

The relationships between size of loading dose and drug concentration, size of maintenance dose and drug concentration, and pulmonary and cutaneous adverse side effects and drug dosage were examined in patients given amiodarone. Amiodarone and metabolite concentrations in plasma and red cell samples were measured by specific high-pressure liquid chromatography. During drug loading, a daily dose schedule of 1600 mg/day produced significantly higher drug concentrations than did a loading dose schedule of 800 mg/day. During maintenance therapy, amiodarone dosage correlated with drug concentrations but with a wide interpatient variability for any given dosage level. The ratio of desethylamiodarone to amiodarone remained relatively constant over different dosage or drug concentration ranges, but increased with duration of treatment, suggesting a time-dependent metabolic function that may be analogous to the time-dependent attainment of maximal antiarrhythmic effect. The occurrence of pulmonary toxicity from amiodarone was not related to duration of treatment or cumulative dose of drug, buy may relate to the magnitude of the maintenance dose of amiodarone. Blue skin discoloration occurred in 19 (36%) of 53 patients receiving amiodarone for longer than 17 months, and may relate to the cumulative dose.

Topics: Amiodarone; Benzofurans; Dose-Response Relationship, Drug; Humans; Lung Diseases; Pigmentation Disorders; Time Factors

Two patients in chronic renal failure receiving amiodarone for the treatment of refractory arrhythmias were commenced on dialysis, in one case, intermittent peritoneal dialysis, in the other, haemodialysis. Plasma concentrations of amiodarone and its desethyl metabolite were consistent with the dose received, whilst neither compound was recovered in the dialysate. In these patients and in 10 additional patients with normal renal function taking amiodarone, only negligible amounts of either compound were detected in urine. These findings suggest that amiodarone may be a suitable antiarrhythmic agent for use in patients with chronic renal failure.

Topics: Amiodarone; Arrhythmias, Cardiac; Benzofurans; Female; Humans; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis; Renal Dialysis

A high-performance liquid chromatographic (HPLC) method utilizing hexane extraction and a normal bonded phase column (NH2-alkylamine) was developed to measure serum concentrations of amiodarone and its N-deethylated metabolite. A single analysis requires 8 min. The one-step extraction efficiencies of amiodarone and the internal standard are greater than 90%. The method is linear between 0.05 and 20.0 micrograms/ml. The average relative standard deviation of the slope of the standard curve is 4% and the single day coefficient of variation is 3.2%. The use of hexane extraction for sample cleanup and a bonded phase column for chromatography result in a sensitive and reproducible system well suited to laboratories monitoring serum concentrations of multiple drugs by HPLC. A preliminary study has shown the assay to be useful for the investigation of the pharmacokinetics of this agent.

Topics: Adult; Amiodarone; Benzofurans; Chromatography, High Pressure Liquid; Half-Life; Humans; Kinetics; Male; Middle Aged

The time course of myocardial uptake and disposition of amiodarone was studied after both acute i.v. and chronic oral administration. In addition, the myocardial disposition of a metabolite, N-desethylamiodarone, was studied after chronic oral amiodarone administration. After i.v. administration, the plasma concentrations of amiodarone fell rapidly; however, peak myocardial concentrations were not observed until 10 to 30 min after administration. Amiodarone was highly concentrated in the myocardium; the average (+/- S.D.) myocardial/plasma concentration ratio between 2 and 6 hr after administration was 89 +/- 32. Although there was significant interanimal variability, there was relative consistency over time in the ratio for each dog during this time period. Although no metabolite (N-desethylamiodarone) was detected in the plasma after the single i.v. dose, it was present in both plasma and myocardial samples after chronic oral therapy. Mean steady-state plasma concentrations of amiodarone and N-desethylamiodarone ranged from 0.62 to 1.63 micrograms/ml and 0.19 to 0.43 micrograms/ml, respectively. These studies show that the myocardial disposition kinetics of amiodarone are different from other drugs studied and both amiodarone and its N-desethyl metabolite accumulate extensively in the myocardium.

Topics: Administration, Oral; Amiodarone; Animals; Benzofurans; Dogs; Female; Injections, Intravenous; Male; Myocardium; Time Factors

A rapid and reliable high-performance liquid chromatographic (HPLC) assay has been developed for the measurement of the antiarrhythmic drug, amiodarone (A), and its metabolite, N-desethyl-amiodarone (NDA), in serum. The procedure involves addition of absolute ethanol to serum, previously adjusted to pH 6, followed by centrifugation. The supernatant is analyzed by reverse-phase HPLC with ultraviolet-visible detection. There is no intereference from endogenous substances or other commonly used antiarrhythmic agents. The mean overall accuracy of the HPLC assay is 96.9 +/- 9.1 (SD)% (n = 37) for A over the concentration range 0.10-10.00 micrograms/mL, and 99.8 +/- 4.8 (SD)% (n = 32) for NDA over the concentration range 0.10-7.50 micrograms/mL. The within-day coefficient of variation is less than 7% for A and NDA. The lower limit of quantitative sensitivity is 0.10 micrograms/mL for A and NDA, and the lower limit of qualitative detection is 1.0 ng for both compounds.

Topics: Amiodarone; Benzofurans; Chromatography, High Pressure Liquid; Humans

A simple and sensitive high-performance liquid chromatographic method for the simultaneous assay of amiodarone and desethylamiodarone in plasma, urine and tissues has been developed. The method for plasma samples and tissue samples after homogenizing with 50% ethanol, involves deproteinization with acetonitrile containing the internal standard followed by centrifugation and direct injection of the supernatant into the liquid chromatograph. The method for urine specimens includes extraction with a diisopropyl ether-acetonitrile (95:5, v/v) mixture at pH 7.0 using disposable Clin-Elut 1003 columns, followed by evaporation of the eluate, reconstitution of the residue in methanol-acetonitrile (1:2, v/v) mixture and injection into the chromatograph. Separation was obtained using a Radial-Pak C18 column operating in combination with a radial compression separation unit and a methanol-25% ammonia (99.3:0.7, v/v) mobile phase. A wavelength of 242 nm was used to monitor amiodarone, desethylamiodarone and the internal standard. The influence of the ammonia concentration in the mobile phase on the capacity factors of amiodarone, desethylamiodarone and two other potential metabolites, monoiodoamiodarone (L6355) and desiodoamiodarone (L3937) were investigated. Endogenous substances or a variety of drugs concomitantly used in amiodarone therapy did not interfere with the assay. The limit of sensitivity of the assay was 0.025 micrograms/ml with a precision of +/- 17%. The inter- and intra-day coefficient of variation for replicate analyses of spiked plasma samples was less than 6%. This method has been demonstrated to be suitable for pharmacokinetic and metabolism studies of amiodarone in man.

Topics: Amiodarone; Benzofurans; Chromatography, High Pressure Liquid; Humans; Kidney; Myocardium

Desethylamiodarone has been identified as the principal lipophilic metabolite of amiodarone present in plasma specimens from amiodarone-treated patients. This structure has been confirmed by probe-injection mass spectrometry of column effluent fractions and comparison with the authentic compound using both chromatographic and mass spectrometric techniques. Although there is no information available as to the pharmacological activity of desethylamiodarone in man, the plasma concentrations of this metabolite attained during chronic amiodarone therapy are similar to those of the parent compound (0.1-4 mg litre-1).

Topics: Amiodarone; Benzofurans; Chromatography, High Pressure Liquid; Gas Chromatography-Mass Spectrometry; Humans

Topics: Amiodarone; Benzofurans; Chromatography, High Pressure Liquid; Humans; Microchemistry

A high-performance liquid chromatographic technique is described for the measurement of amiodarone and its desethyl metabolite in plasma. Preliminary observations are presented on the concentrations of metabolite found during the early stages of chronic amiodarone therapy. A case history is outlined in which noncompliance during treatment with amiodarone was confirmed by measurement of the ratio of desethylamiodarone to amiodarone concentrations.

Topics: Amiodarone; Benzofurans; Chromatography, High Pressure Liquid; Female; Humans; Middle Aged; Patient Compliance; Time Factors