Serum Amiodarone Concentrations Research Articles

Increased serum amiodarone concentration in hypertriglyceridemic patients: Effects of drug distribution to serum lipoproteins.

Amiodarone and its main metabolite, desethylamiodarone (DEA), are highly distributed to serum lipoproteins such as very‐low‐density lipoprotein (VLDL) and low‐density lipoprotein (LDL), which are the carriers of triglyceride and cholesterol. This study aimed to investigate the association of serum concentrations of amiodarone and DEA with the levels of serum lipids in terms of drug distribution to lipoprotein fractions in patients with hyperlipidemia. Total serum concentrations of amiodarone and DEA were examined in 116 patients receiving amiodarone for tachyarrhythmias. The concentration‐to‐dose (C/D) ratio of amiodarone positively correlated with the level of serum triglyceride (rs = 0.541, p < 0.001) and was higher in the hypertriglyceridemic state than in normotriglyceridemic state (479 ± 211 vs. 320 ± 161, p < 0.001). No correlation was found between the C/D ratio of DEA and serum triglyceride levels (rs = 0.272), although higher values were observed in the hypertriglyceridemic state (322 ± 125 vs. 285 ± 143, p < 0.001). In the hypertriglyceridemic state, the distribution of amiodarone increased in LDL/VLDL fraction and decreased in high‐density lipoprotein and albumin fractions. The ratio of serum amiodarone to serum DEA, a metabolic ratio of amiodarone, positively correlated with serum triglyceride levels (rs = 0.572, p < 0.001) and was higher in the hypertriglyceridemic state, suggesting that amiodarone metabolism decreased in hyperlipidemia. The results of this study reveal that serum concentrations of amiodarone increase in the hypertriglyceridemic state through the increased lipoprotein‐binding and decreased metabolism of amiodarone.

Pharmacokinetic Disposition of Amiodarone When Given with an Intralipid Rescue Strategy.

While the antiarrhythmic drug amiodarone is commonly used in clinical practice, it has a narrow therapeutic index that can lead to acute overdose. One proposed method to deal with this toxicity is lipid emulsion therapy, which may potentially quench the free amiodarone in blood and prevent its further distribution to target organs and tissues. In this study, we utilize an established swine model to examine the effects of Intralipid™ (IL) administration for acute amiodarone toxicity. A total of 14 pigs received an overdose of intravenous amiodarone. After twenty minutes, half of the pigs (n = 7) received IL while the control group (n = 7) received normal saline. Serum concentrations of amiodarone were then analyzed using a validated high-performance liquid chromatography (HPLC) method. Noncompartmental pharmacokinetic analyses were performed on the observed concentrations. There were no statistical differences in the area under the concentration time curve (6 h) or clearance, but there was a difference in the half-life between the two groups (3.12 vs. 0.85 h, p = 0.01). The administration of IL did not statistically change the overall exposure of amiodarone in the blood in the first 6 h; however, trends toward prolonged blood retention in the IL group were seen.

Therapeutic monitoring of amiodarone and desethylamiodarone after surgical ablation of atrial fibrillation-evaluation of the relationship between clinical effect and the serum concentration

BackgroundAssociation between clinical effect and serum concentration of amiodarone (AMI) and its active metabolite desethylamidarone (DEA) in patients after surgical ablation (SA) of atrial fibrillation (AF) has not yet been studied. AimsWe wanted to find a correlation between AMI and DEA serum concentration and maintaining sinus rhythm (SR) after SA of AF. MethodsSixty eight patients with AF who had undergone surgical ablation between 2014 and 2017 were included in a single-centre, prospective, observational study. Maintaining of SR was evaluated by standard 12-lead ECG and 24-hour Holter ECG monitoring at months 1, 3, 6 and 12 following surgery. Therapeutic monitoring of AMI and DEA concentrations was done to optimize therapy and adverse effects were followed up. ResultsWe have noticed a high success rate in maintaining of SR (overall 83%). The median of serum concentration of AMI was 0.81 mg/L (range 0.16–2.35 mg/L) and DEA 0.70 mg/l (range 0.19–2.63 mg/L). No significant differences were found in the serum concentratration of AMI, DEA or DEA/AMI concentratration ratios between patients with SR and persistent supraventricular tachyarrhythmia except on the second outpatient visit. We observed significant correlation between serum concentration of DEA and thyroid-stimulating hormone elevation. ConclusionWe confirmed the efficacy of AMI and DEA at the measured serum concentrations. However, analysis of these concentrations alone cannot replace assessment of the clinical response for treatment. Establishment of individual AMI (and DEA) concentrations at which the optimal therapeutic response is achieved seems to be advantageous. Therapeutic monitoring of AMI and DEA is helpful in personalised pharmacotherapy after SA of AF.

Analysis of Pharmacokinetic Interaction Between Amiodarone/Desethylamiodarone and Metoprolol

Amiodarone (AM) is the most effective antiarrhythmic drug and its major metabolite desethylamiodarone (DEA) is pharmacologically effective as well. A β1 blocker metoprolol (M) is metabolized to alpha-hydroxymetoprolol (OH-M) by CYP2D6 and both AM and DEA inhibit this enzyme. We analysed interaction between amiodarone/ desethylamiodarone and metoprolol. We analyzed retrospectively 69 serum concentrations of AM, DEA, M and OH-M measured by HPLC method with UV or fluorescent detection from 29 patients (years 2014-2015). We estimated the concentration/dose ratio of metoprolol, metabolic ratio of M/OH-M and OH-M/M, and metoprolol clearance (Cl) and elimination half-time (t1/2) depending on concentrations of AM, DEA and sum AM+DEA. Phenotypization of patients was performed by metabolic ratio (MR) of M/OH-M concentrations. Statistically significant correlation was observed between concentration/dose ratio of metoprolol and concentrations of both AM and DEA as well as between metabolic ratio M/OH-M and concentrations of both sum AM+DEA and DEA itself. No statistically significant correlation was found between t1/2 a Cl of metoprolol and concentrations of AM or DEA. Phenotypization of CYP2D6 divided individual samples into groups with MR<1.0 (n=17) and MR 1.0-10.5 (n=7) for serum taking after metoprolol administration and with MR<1.0 (n=31) and MR 1.0-10.5 (n=7) for serum taking before metoprolol administration. We showed that an increasing concentrations of amiodarone and desethylamiodarone led to lower dose of metoprolol to achieved the same serum concentration. Increase of DEA and sum of AM+DEA concentrations led to decrease of metoprolol metabolization by inhibition of CYP2D6. The results indicate that important drug-drug interaction between metoprolol and amiodaron is due to inhibition of CYP2D6, mainly by DEA. Therefore wen the combination of drugs is administered careful therapeutic monitoring of not only metoprolol but also of amiodarone including DEA is recommended.

Corneal Densitometry as a Novel Technique for Monitoring Amiodarone Therapy

The clinical efficacy and toxicity of amiodarone may be determined more effectively by tissue deposition than by levels of the agent in serum. Therefore, corneal densitometry might be useful for therapeutic monitoring. The aim of the study is to evaluate Scheimpflug corneal densitometry in patients with amiodarone keratopathy (AK). Comparative case series. Sixty-six patients receiving amiodarone therapy and 66 healthy controls were consecutively enrolled in this study. Patients were examined using the Oculus Pentacam (Wetzlar, Germany). Densitometry data from different corneal layers and different annuli were extracted, analyzed, and compared with densitometry values of healthy controls. Duration of treatment, cumulative dose, Orlando stage (slit-lamp biomicroscopy), and serum concentrations of amiodarone and N-desethylamiodarone also were determined, and the correlation to different densitometry data was evaluated. The total corneal light backscatter at total corneal thickness and at total diameter was significantly higher in the amiodarone group compared with the control group (AK group: 28.3±5.2; control group: 24.4±4.2; P < 0.001). Upon dividing the corneal surface into different layers at total thickness, the differences were significant in all layers (P < 0.001). The serum concentrations of the metabolite N-desethylamiodarone correlate with densitometry values, especially in the 0- to 2-mm annulus in the anterior layer (r= 0.419; P= 0.001), whereas the cumulative dose and duration of treatment correlate significantly with the densitometry values in the 0- to 2-mm annulus at total thickness (P= 0.014 and P= 0.022, respectively). Corneal densitometry is a useful, objective method for quantifying AK and can help in monitoring amiodarone therapy. The serum concentration of the active metabolite N-desethylamiodarone correlates with the extent of keratopathy in the anterior layer, whereas chronic changes in the stroma correlate with the cumulative dose and duration of treatment.

体外循環施行前後ではアミオダロンおよびアミオダロン代謝物の血中濃度変化は認められない&amp;emsp;～ 1症例報告 ～

体外循環施行前後ではアミオダロンおよびアミオダロン代謝物の血中濃度変化は認められない&amp;emsp;～ 1症例報告 ～

Influence of peroxisome proliferator-activated receptor-alpha (PPARα) activity on adverse effects associated with amiodarone exposure in mice

Although amiodarone is the most effective antiarrhythmic agent currently available, concerns regarding adverse effects, including liver, lung and thyroid toxicity, often limit its use. Previously, we reported that amiodarone-induced hepatic steatosis in mice was associated with an upregulation of target genes modulated by peroxisome proliferator-activated receptor-alpha (PPARα). Because amiodarone does not directly stimulate PPARα, target gene induction may reflect a compensatory reaction countering some adverse effects of amiodarone. To test this, we examined co-treatment with the PPARα agonist, fenofibrate, and amiodarone in both PPARα(+/+) and PPARα(−/−) mice. Amiodarone treated PPARα(−/−) mice exhibited significantly greater weight loss and higher serum aspartate aminotransferase (AST) compared to PPARα(+/+) mice. Fenofibrate co-treatment reduced weight loss in amiodarone treated PPARα(−/−) mice, but not PPARα(+/+) mice. Fenofibrate stimulation of PPARα reduced serum amiodarone concentrations in normal mice. Serum amiodarone concentrations were higher in mice without PPARα expression given at 40–80 mg/kg amiodarone doses. These results are consistent with a protective influence of PPARα in reducing amiodarone-induced hepatic toxicity. In addition to PPARα-dependent effects, fenofibrate also demonstrated PPARα-independent actions that suggest a complex interaction modulating both hepatic lipid metabolism and amiodarone disposition. Further studies of the beneficial effect of fenofibrate and the interplay between lipid metabolism and amiodarone pharmacokinetics are required.

Toxicity in Doberman Pinchers with Ventricular Arrhythmias Treated with Amiodarone (1996–2005)

Asymptomatic Doberman Pinschers with dilated cardiomyopathy (DCM) often die suddenly owing to ventricular tachycardia that degenerates into ventricular fibrillation. A safe and effective antiarrhythmic drug treatment is needed. This will require a large, well-controlled, prospective study. Amiodarone toxicity is common in Dobermans with occult DCM and ventricular tachyarrhythmias refractory to antiarrhythmia therapy. Infrequent monitoring of hepatic function is inadequate. Frequent monitoring may be useful to determine dogs in which the dosage should be decreased or the drug withdrawn. Medical records from the University of Georgia and Cornell University were searched for Doberman Pinschers diagnosed with preclinical DCM that received amiodarone for severe ventricular arrhythmias refractory to other antiarrhythmic agents. Echocardiographic data, Holter recording data, hepatic enzyme serum activity, and serum amiodarone concentrations were recorded. The presence of clinical signs of toxicity was recorded. Serum amiodarone concentrations were obtained in some dogs. Reversible toxicity was identified in 10 of 22 (45%) dogs. Adverse effects from amiodarone were common and were, in part, dosage related. Patients should be monitored for signs of toxicity and liver enzyme activity should be measured at least monthly.

Effect of obesity on serum amiodarone concentration in Japanese patients: population pharmacokinetic investigation by multiple trough screen analysis

To evaluate the influence of obesity on pharmacokinetics of amiodarone (AMD) using Non-Linear Mixed Effects Modelling (NONMEM) in Japanese patients treated with oral therapy. Serum concentrations of AMD were determined by high performance liquid chromatography. One hundred and fifty-one trough concentrations from 23 patients receiving repetitive oral AMD were collected. Body mass index (BMI) and body fat percentage were measured. Estimates generated using NONMEM indicated that the clearance of AMD was influenced by BMI, age and daily dosage of AMD. The final pharmacokinetic model was CL (L/h) = 0*16 * TBW * 0.53(AGE >or= 65 ) * 0*78(BMI >or= 25) * DD(0.51), V(d) (L) = 10*2 * TBW, where CL is total body clearance, TBW is total body weight (kg), DD (mg/kg/day) is daily dosage of AMD, AGE (years) >or=65 = 1 for patient was 65 years old or over and 0 otherwise, BMI (kg/m(2)) >or=25 = 1 for patient was 25 kg/m(2) or over and 0 otherwise and V(d) is apparent volume of distribution. The clearance of AMD decreased significantly by 22.3% with a BMI higher than 25 kg/m(2). The clearance of AMD also decreased significantly by 46.9% when patient age was more than 65 years. Population pharmacokinetic analysis confirms that obesity affects the pharmacokinetics of AMD.

Prospective evaluation of serum amiodarone concentrations when administered via a nasogastric tube into the stomach conduit after transthoracic esophagectomy

Background: Atrial fibrillation occurs in up to 46% of patients following esophagectomy; amiodarone may be used for prophylaxis or treatment in these patients. There are few data regarding drug absorption following esophagectomy. Objective: The aim of this study was to determine serum amiodarone concentrations when the drug is administered into the stomach conduit following esophagectomy. Methods: Patients who underwent noncardiac thoracic surgery were enrolled in this prospective, controlled study. One group of patients underwent esophagectomy, and a second group of patients comprised a control group who underwent pulmonary resection (PR). A continuous IV amiodarone infusion (0.73 mg/min) was initiated at anesthesia induction and continued for 24 hours (total IV dose 1050 mg), ollowed by 400 mg via a nasogastric tube (in the esophagectomy group) or orally (in the PR group) every 12 hours for 6 days. Blood samples for determination of serum amiodarone concentrations were obtained at completion of the infusion (postoperative day [POD] 1), and before the third (POD 2) and seventh (POD 4) enteral doses. Results: A total of 27 patients were enrolled (esophagectomy group, 13 patients; PR group, 14 patients). Patients in the 2 groups had statistically similar ages (mean [SD], 60 [10] vs 53 [10] years; P = 0.07) and proportions of men (12/13 [92%] vs 8/14 [57%]; P = 0.08). Patients in the 2 groups were statistically similar with respect to race (white, 13/13 [100%] vs 13/14 [93%]) and preoperative weight (mean [SD], 83.3 [11.5] vs 77.7 [18.6] kg). On POD 1, age-adjusted and sex-adjusted serum amiodarone concentrations were not significantly different in the esophagectomy group versus the PR group (mean [SD] 0.65 [0.22] vs 0.84 [0.20] μg/mL). Mean (SD) serum amiodarone concentrations were significantly lower in the esophagectomy group on POD 2 (0.35 [0.27] vs 0.60 [0.18] μg/mL; P = 0.02) and on POD 4 (0.30 [0.34] vs 0.87 [0.16] µg/mL; P < 0.001). Serum amiodarone concentrations were undetectable in 33% and 50% of patients in the esophagectomy group on PODs 2 and 4, respectively, compared with 0% in the PR group (both, P = 0.03). Conclusions: Serum amiodarone concentrations were significantly lower (and in some cases undetectable) when the drug was administered via a nasogastric tube into the stomach conduit in patients after esophagectomy compared with those concentrations after oral administration in a PR population. These data were presented as a poster presentation at the Spring Practice and Research Forum, American College of Clinical Pharmacy, April 9, 2006, Monterey, California.

Elevation of Serum Amiodarone Concentrations in Cardiac Sarcoidosis and Dilated Cardiomyopathy Patients

Elevation of Serum Amiodarone Concentrations in Cardiac Sarcoidosis and Dilated Cardiomyopathy Patients

Amiodarone Treatment of Junctional Ectopic Tachycardia in a Neonate Receiving Extracorporeal Membrane Oxygenation

To describe the administration of amiodarone and the resulting serum concentrations in a neonate receiving extracorporeal membrane oxygenation (ECMO). A 3463 g, 38 week gestational age male diagnosed with tetralogy of Fallot developed junctional ectopic tachycardia (JET) and required ECMO support following cardiac surgery. The patient continued to show JET despite cooling, pacing, and intravenous amiodarone infusion, with the dose initiated at 10 microg/kg/min. Sinus rhythm was achieved following 5 days of treatment, additional amiodarone boluses, and an increase in the infusion rate to 20 microg/kg/min. Two serum concentrations of amiodarone were obtained during therapy. On day 4, the concentration was 0.9 mg/L at the 20 microg/kg/min infusion rate; a bolus dose of 5 mg/kg was administered 1 hour later. The serum concentration the following day, with the infusion rate unchanged, was 2 mg/L. ECMO is used increasingly postoperatively in patients with congenital cardiac abnormalities. The incidence of JET following repair of tetralogy of Fallot is 22%. Despite the minimal information on the pharmacokinetics of amiodarone in neonates, it has been used in doses up to 20 microg/kg/min for the treatment of postoperative JET. As of August 25, 2006, we found no reports describing its dosage and use in patients undergoing ECMO. The delivery of amiodarone to a patient receiving ECMO may be complicated by the administration of large blood volumes, circuit changes, and binding to the circuit. Neonates receiving ECMO may require larger amiodarone doses to achieve a therapeutic effect. Further investigation is required to define the pharmacokinetics and pharmacodynamics of amiodarone in neonates receiving ECMO.

Serum amiodarone and desethylamiodarone concentrations following nasogastric versus oral administration

Hospitalized patients unable to ingest anything by mouth require nutritional support by enteral feeding and administration of drugs through a nasogastric tube inserted into the digestive tract. Nasogastric administration of amiodarone may not always be equivalent to oral administration of amiodarone. We collected 162 observations of serum amiodarone and desethylamiodarone metabolite concentrations from 93 patients within 60 days of starting treatment with amiodarone. Eight patients were given the drug nasogastrically and 85 patients, orally. The two groups, were compared in terms of their serum concentration/(dose/weight) (C/D) value. A ratio of serum amiodarone concentration to serum desethylamiodarone concentration (AMD/DEA) was calculated for each sample. In addition, the percentage drug recovery after nasogastric administration of amiodarone was analysed. Significant differences were observed in C/D values of amiodarone and desethylamiodarone and in AMD/DEA values of patients given amiodarone orally when compared with those given the drug nasogastrically. The C/D values of patients who received their medication nasogastrically were approximately 30% of the C/D values of patients who received their medication orally. Approximately 70% of the drug was recovered after it had passed through the nasogastric tube. To achieve similar concentrations, an approximately 3-fold increase in dosage of amiodarone was required when patients were given the drug nasogastrically rather than orally. This suggests that the absorption of amiodarone following nasogastric administration is poor when compared with oral administration. Therapeutic drug monitoring is necessary to optimize dose particularly during the early stages of amiodarone therapy.

Pharmacokinetic Characteristics of Amiodarone in Long-Term Oral Therapy in Japanese Population

To evaluate the pharmacokinetic properties and an optimum dose schedule of amiodarone in long-term oral therapy, serum concentrations of amiodarone and its metabolite, desethylamiodarone, were monitored from 345 Japanese inpatients who received amiodarone therapy for a variety of cardiac arrhythmias. Serum amiodarone and desethylamiodarone concentrations were determined by high performance liquid chromatography system. It was observed that the amiodarone and desethylamiodarone concentrations gradually increased with time. The frequency distribution in the amiodarone clearance of 245 subjects, who received fixed maintenance amiodarone therapy for at least 6 months, was nearly a unimodal one. The variation in the ratio of desetylamiodarone to amiodarone concentration in serum was very small. Although no differences in age, dose, dose duration, amiodarone or desethyamiodarone concentration or ratio were observed between men and women: however, the mean amiodarone clearance of women was significantly higer than that of men. The laboratory data were mostly within normal values and no significant relations were observed between serum amiodarone concentration and clinical laboratory data. These results suggest that the individual variation in pharmacokinetics of amiodarone is comparatively small, which might be sufficient to decide that the maintenance dose was the same one (200 mg/d) in long-term oral amiodarone therapy.

Amiodarone Interaction Time Differences with Warfarin and Digoxin

Background: Amiodarone has pharmacokinetic and pharmacodynamic interactions with various therapeutic agents. The mechanism of interaction between warfarin and amiodarone is the inhibition of warfarin metabolism by amiodarone, and that between digoxin and amiodarone is the inhibition of digoxin transport by amiodarone. Objective: To investigate the pharmacokinetic magnitude of the time differences between amiodarone–warfarin and amiodarone–digoxin interactions. Methods: Amiodarone was administered concomitantly to 79 inpatients who had been receiving fixed-maintenance doses of warfarin or digoxin. Seventy-seven inpatients were prescribed warfarin therapy, and 54 inpatients were prescribed digoxin therapy. To determine serum concentrations of the warfarin enantiomers digoxin, amiodarone, and desethylamiodarone blood samples were obtained with coadministration of amiodarone. Serum S- and R-warfarin, amiodarone, and desethylamiodarone concentrations were measured by HPLC methods, and serum digoxin concentrations were measured by a fluorescence polarization immunoassay. Results: A remarkable decrease of S-warfarin clearance was observed within approximately the first 2 weeks after coadministration of amiodarone. Only a small decrease in R-warfarin clearance was observed. Digoxin clearance was gradually decreased with time, and a good reverse correlation was obtained between amiodarone or desethylamiodarone concentrations and digoxin clearance. Conclusions: Relatively short-term monitoring of warfarin clearance is required when amiodarone is coadministered. Long-term monitoring of digoxin serum amiodarone and desethylamiodarone concentrations is necessary to detect the amiodarone–digoxin interaction.

Intravenous amiodarone: pharmacology, pharmacokinetics, and clinical use.

To review the clinical pharmacology, pharmacokinetics, and clinical efficacy and safety of intravenous amiodarone. Articles were identified through a computer search of the English-language literature using MEDLINE (KR Information OnDisc) and the search term amiodarone. Additional articles were identified through examination of the bibliographies of the articles initially retrieved. Relevant or representative animal studies, clinical trials, and case reports were selected for evaluation. Particular emphasis was placed on studies pertaining to the use of intravenous amiodarone in treatment-refractory ventricular fibrillation (VF) and hemodynamically unstable ventricular tachycardia (VT). The literature was assessed for adequate description of patients, study methodologies (e.g., study design, number of patients), and outcomes. Amiodarone is an unusual class III antiarrhythmic that produces each of the four main types of antiarrhythmic action in addition to other effects, such as vasodilatory, selective antithyroid, and other activities that may be therapeutically relevant. Amiodarone pharmacokinetics demonstrate extensive interpatient variability and are characterized by wide tissue distribution (steady-state volume of distribution 40-84 L/kg), slow total body clearance (90-158 mL/h/kg), long terminal elimination half-life (20-47 d), and extensive hepatic metabolism. The onset of maximal antiarrhythmic effect is a function of both amiodarone dosage and time. The high plasma concentrations achieved with intravenous dosing do not fully replicate the electrophysiologic effects observed following long-term oral administration, particularly with respect to class III activity. Available data suggest that intravenous amiodarone is associated with an efficacy rate of 50% or more in treatment-refractory VT/VF, and has a relatively rapid (2-24 h) onset of action. The drug is relatively well tolerated, but close hemodynamic, electrocardiographic, and hepatic function monitoring are required. The value of using amiodarone serum concentrations to guide therapy remains uncertain. Intravenous amiodarone is an effective, relatively safe antiarrhythmic for the treatment of recurrent, hemodynamically unstable VT/VF refractory to other drug therapy in the acute care setting.

Creatinine elevation in patients receiving amiodarone correlates with serum amiodarone concentration.

Serum creatinine and drug concentrations were measured at 0, 1, 2, 3, 6, 9 and 12 months in 30 consecutive patients started on amiodarone. In 28 of these patients with no obvious cause for altered renal function, mean serum creatinine increased to 11% above baseline (P < 0.005). Rising creatinine concentrations correlated with amiodarone concentrations (y = 93.9 + 8.6x, r = 0.51, P < 0.0001). When assessing elevation of serum creatinine in a patient receiving amiodarone, physicians should be aware that it may be related to this drug.

Effect of Phenytoin on the Clinical Pharmacokinetics of Amiodarone

Five healthy male volunteers were given oral amiodarone hydrochloride, 200 mg per day for 6 1/2 weeks, to determine its effects on the pharmacokinetics of both intravenous and oral phenytoin. Predose amiodarone and N-desethylamiodarone serum concentrations were obtained weekly during weeks 2-6. Amiodarone serum concentrations (ASC) increased during weeks 2-4 and then decreased sharply during weeks 5-6 when oral phenytoin, 2-4 mg/kg/day, was co-administered. In addition, N-desethylamiodarone serum concentrations (DEASC) exceeded corresponding ASC during weeks 5-6 whereas during weeks 2-4, DEASC were less than ASC. Because of the long elimination half-life for amiodarone previously reported in healthy volunteers after single doses of amiodarone and the frequent administration of amiodarone associated with this half-life, a modified equation for a continuous infusion was used to describe each subject's ASC versus time data. Pre-phenytoin ASC were fitted to an appropriate function to predict ASC during weeks 5-6 assuming no interaction. Observed versus predicted ASC were compared for weeks 5 and 6. Observed ASC during weeks 5 and 6 were (mean +/- SD) 0.25 +/- 0.09 micrograms/mL and 0.19 +/- 0.07 micrograms/mL, respectively. Corresponding predicted ASC were 0.36 +/- 0.12 micrograms/mL (P = .011) and 0.38 +/- 0.13 micrograms/mL (P = .004). These represented percent differences of 32.2 +/- 12.5% and 49.3 +/- 5.6% for weeks 5 and 6, respectively. Assuming there were no changes in the bioavailability of amiodarone during continuous administration, these findings strongly suggest induction of amiodarone metabolism by phenytoin. The clinical significance of this interaction remains to be determined.

Relation of amiodarone hepatic and pulmonary toxicity to serum drug concentrations and superoxide dismutase activity

Hepatic enzymes, pulmonary function, serum amiodarone and desethylamiodarone (DEA) concentrations and erythrocyte superoxide dismutase (SOD) activity were monitored at regular intervals for 1 year in 30 patients receiving amtodarone. Subclinical hepatotoxicity developed in 5 patients. These patients had higher baseline alanine transaminase values (42.6 ± 6.8 vs 22.9 ± 1.8 U/liter) and had an increase in serum aspartate transaminase from 27 ± 4.1 at baseline to 147 ± 77.3 U/liter at 12 months. The other patients had little variation in aspartate transaminase. Six patients with normal baseline carbon monoxide diffusing capacity had subclinical pulmonary toxicity develop with a mean decrease in diffusing capacity to 0.7 ± 0.05 of the baseline value, which correlated with decreasing erythrocyte SOD activity. Mean carbon monoxide diffusing capacity and SOD activity remained unchanged in the other patients. The mechanisms of hepatic and pulmonary injury remain unknown, but appear to be associated with exposure to higher total serum concentrations of amiodarone plus DEA. Patients who had hepatic and/or pulmonary abnormalities develop received higher doses of amiodarone (440 ± 27 vs 340 ± 18 mg/day), but also had a higher amiodarone:DEA ratio suggesting that dose-dependent kinetics contributed to the higher concentrations. Elevated baseline alanine transaminase may indicate increased risk for hepatotoxicity while a progressive decrease in erythrocyte SOD may be an early indication of pulmonary toxicity. The latter finding indicates a need to investigate the role of free radicals in the pathogenesis of amiodarone pulmonary toxicity.

Correlation of amiodarone dosage, heart rate, QT interval and corneal microdeposits with serum amiodarone and desethylamiodarone concentrations

Pharmacokinetic-dynamic relations for amiodarone have been difficult to define. Few studies have successfully correlated serum amiodarone concentration with either dose or pharmacodynamic effects. Reduction in heart rate, prolongation of corrected QT interval and accumulation of corneal microdeposits are 3 clinical effects well suited for making kinetic-dynamic comparisons because they occur in virtually all patients receiving amiodarone. Data on heart rate, corrected QT interval, corneal microdeposits, cumulative dose and serum concentrations of amiodarone and desethylamiodarone (DEA) were collected over the course of 1 year after initiation of therapy in 27 patients (mean age 55.4 ± 2.35 years). Mean elimination half-lives in this study population were 56 days for amiodarone and 129 days for DEA, as estimated from cumulation kinetics without drug withdrawal. The extremely long half-lives of amiodarone and DEA make demonstration of steady-state concentration-response relations difficult. A new approach using analysis of sequential data before steady-state reveals general relations between dose, DEA concentration and 3 clinically observable effects of amiodarone. A linear relation was evident between DEA concentration and log mean cumulative amiodarone dose (mg/kg) for the population. The steep segments of the concentration-response curves for heart rate, microdeposits and corrected QT interval occurred at low, medium and high serum amiodarone and DEA concentrations, respectively. Patients not developing a decrease in heart rate or corneal microdeposits likely have very low serum drug concentrations and may not be adequately treated. The monitoring of heart rate, corrected QT interval and corneal microdeposits as an aid to assessing adequacy of amiodarone therapy requires further study.