Pharmacokinetics of desethylamiodarone in the rat after its administration as the preformed metabolite, and after administration of amiodarone

The pharmacokinetics of desethylamiodarone (DEA), the active metabolite of amiodarone (AM), were studied in the rat after administration of AM or preformed metabolite. Rats received 10 mg/kg of either intravenous or oral AM HCl or DEA base. Blood samples were obtained via a surgically implanted jugular vein cannula. Plasma concentrations were measured by a validated LC/MS method. In all AM treated rats, AM plasma concentrations greatly exceeded those of the formed DEA. The fraction of AM converted to DEA after i.v. administration was 14%. Amiodarone had a significantly lower (approximately 50%) clearance than DEA, although the volume of distribution and terminal phase half-life did not differ significantly. The hepatic extraction ratio of DEA was 0.48, similar to that of AM (0.51). Oral AM demonstrated higher plasma AUC (5.6 fold) and higher C(max) (6.1 fold) than oral DEA and oral bioavailability of AM (46%) was greater than DEA (17%). The estimated fraction of the oral dose of AM converted to DEA was 4.5 fold higher than after i.v. administration, suggesting first-pass formation of DEA from AM. Amiodarone and DEA differed in their pharmacokinetic characteristics mostly due to a higher CL of DEA. With oral dosing, AM appeared to undergo significant presystemic first-pass metabolism within the intestinal tract.     

Presynaptic antisympathetic action of amiodarone and its metabolite desethylamiodarone

Amiodarone has a "reserpine-like" sympatholytic action in the heart. The aims of this study were to test whether desethylamiodarone (DEA), the in vivo bioactive metabolite of amiodarone, has this action and whether this action could be demonstrated in a neuronal preparation. Experiments were performed in intact rats, perfused hearts, or brain synaptosomes treated with DEA and amiodarone, and concentrations of norepinephrine (NE) and dihydroxyphenylglycol (DHPG), the intraneuronal metabolite of NE, were assayed in plasma, coronary effluent, and synaptosomes. In perfused hearts, DEA at 1, 3, and 10 microM increased DHPG overflow by threefold, sixfold, and ninefold, respectively (all p < 0.01 vs. control). DEA at 1 microM was more potent than amiodarone in increasing DHPG overflow. DEA at 1 and 3 microM also inhibited NE release evoked by sympathetic nerve stimulation (p < 0.05). In intact rats, intravenous DEA at 15 mg/kg elicited onefold increase in plasma DHPG level, and oral pretreatment with amiodarone did not interfere with the sympatholytic action of intravenous amiodarone. In synaptosomes, 40-min incubation with amiodarone, DEA (both 10 microM), and reserpine reduced synaptosomal NE content by 42, 45, and 60%, respectively. Thus similar to its parent drug, DEA exerts a presynaptic sympatholytic action in rat hearts in vivo and in vitro. This action of amiodarone and DEA also was observed in synaptosomes.     

Determination of amiodarone and its metabolite desethylamiodarone in human plasma and serum

A liquid chromatographic method for the assay of antiarrhythmic drug amiodarone and its metabolite desethylamiodarone in human plasma or serum has been developed. The method is simple and sufficiently sensitive for pharmacokinetic studies. Amiodarone, desethylamiodarone and added internal standard L 8040 were twice extracted at various pH from serum or plasma. The extract after evaporation was reconstituted in the mobile phase and chromatographed on reversed phase Hibar LiChrosorb RP-8 column with UV detection, at 254 nm. The method is specific and can detect approximately 30 ng of amiodarone and desethylamiodarone in 1 ml of plasma or serum.     

Modulation of calmodulin properties by amiodarone and its major metabolite desethylamiodarone.

Long-term amiodarone therapy is invariably associated with some side effects. Although its mechanism of action, as an antiarrhythmic drug is well understood, the side effect profile of amiodarone is not yet established. To determine possible mechanisms, the interaction of amiodarone and its major metabolite desethylamiodarone with calmodulin was investigated, since calmodulin is known to regulate Ca2+ transport, cell proliferation and the enzymes involved in signal transduction and nucleotide metabolism. The interaction between the drugs and calmodulin was studied by monitoring intrinsic tyrosine fluorescence of calmodulin and by using a fluorescent probe, N-phenyl-1-naphthylamine (NPN). 14C-Chlorpromazine displacement studies were conducted to differentiate the specific binding sites. The effect on the biological activity of calmodulin was determined with calmodulin dependent phosphodiesterase and Ca2(+)-ATPase. The dansyl calmodulin was used as fluorescent probe to study the effect of these drugs on complex formation between calmodulin and phosphodiesterase. Both amiodarone and desethylamiodarone decreased tyrosine fluorescence of calmodulin with IC50 of 4.9 and 4.4 microM respectively and these interactions were Ca2(+)-dependent. NPN fluorescence was also affected in a concentration dependent manner. These drugs also displaced bound 14C-chlorpromazine from calmodulin and the effect was biphasic. However, desethylamiodarone was more potent than amiodarone. The binding of 3H-amiodarone to calmodulin was modified by a variety of compounds, one class of compounds decreased and the other increased 3H-amiodarone binding to calmodulin. Only, desethylamiodarone inhibited the phosphodiesterase activation by calmodulin with IC50 of 13.2 microM without changing the basal enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics and body distribution of amiodarone and desethylamiodarone in rats after oral administration

The pharmacokinetics and body distribution of amiodarone and desethylamiodarone were studied in rats after single oral administration of 100 mg/kg and 200 mg/kg of amiodarone. The time-course of the concentrations of the drug and its main metabolite was determined by high performance liquid chromatography in serum and tissues up to 24 h. The mean absorption half-life of amiodarone was 1.83 h for both dosages and the mean elimination half-life was 15 h after the 100 mg/kg dosage and 105 h after the 200 mg/kg dosage. The mean bioavailability of oral amiodarone ranged from 17% to 60% with an average of 39%. Desethylamiodarone, the major metabolite of amiodarone, was present over the 24 h period of observation in relatively low levels of 30 to 60 ng/ml after the 100 mg/kg dose and 50 to 110 ng/ml after the 200 mg/kg dose respectively, which is circa 4% and 7% of the corresponding parent drug level. Amiodarone is preferentially distributed in decreasing order in lung, liver, thyroid gland, kidney, heart, adipose tissue, muscle tissue and brain. The metabolite desethylamiodarone exhibited a distribution pattern comparable to the parent drug. However, its maximum concentrations in serum and tissues were consistently lower than the corresponding amiodarone concentrations and varied from 18 to 55% (mean 27%), depending on the acute oral dose applied and on the kind of tissue. The amiodarone tissue/serum concentration ratios were high in lung tissue (60-100) and moderate to high in the other tissues except brain (3-60), and indicate an extensive distribution of the drug with the lung as an organ with specific binding sites or uptake mechanisms and adipose tissue as a reservoir with a large storage capacity. The metabolite tissue/serum concentration ratios were very high in lung tissue (500-800), high in renal, thyroid, liver and adipose tissue (80-200) and moderate in the other tissues except for brain (20-60); they indicate a very extensive distribution of desethylamiodarone with, primarily, lung and to some lesser extent kidney, liver and thyroid gland as organs with sites of metabolism and/or specific binding sites or uptake mechanisms and fat as a reservoir for the drug. A marked increase in the accumulation of amiodarone and desethylamiodarone was observed in adipose tissue after chronic oral administration, whereas the rise in kidney and brain was less pronounced and in the remaining tissues it was insignificant. Our data suggest that the rat is a good model for describing the single oral dose pharmacokinetics and body distribution of amiodarone and desethylamiodarone in man.     

Disposition of ethanol and its proximate metabolite, acetaldehyde, in the near-term pregnant ewe for short term maternal administration of moderate-dose ethanol

The effect of short term maternal ethanol administration on the disposition of ethanol in the ovine maternal-fetal unit was determined. Eleven conscious instrumented near-term pregnant ewes (between 125 and 134 days of gestation; term, 147 days) received 1-hr iv infusion of 1 g of ethanol.kg of maternal body weight-1.day-1 for six days (N = 6 ewes) or an equivalent volume of saline for six days (N = 5 ewes). On the seventh day, the ethanol- and saline-pretreated animals were administered 1 g of ethanol.kg of maternal body weight-1. Ethanol and acetaldehyde concentrations were determined by headspace GLC in maternal blood, fetal blood, and amniotic fluid samples obtained at selected times during the 14-hr study. The data demonstrated that short term maternal administration of once-daily moderate dose ethanol did not produce major changes in the disposition of ethanol and its proximate metabolite, acetaldehyde, in the maternal, fetal, and amniotic fluid compartments during near-term ovine pregnancy.     

Effects of amiodarone and its metabolite, desethylamiodarone, on the electrophysiologic properties of isolated cardiac muscle

The electrophysiologic (EP) effects of chronically administered amiodarone (AM) is known, but the nature of its acute effects are unclear. Whether the delayed onset of AM action is due to its metabolite, desethylamiodarone (DAM), is also uncertain. By standard microelectrode techniques in isolated canine ventricular muscle (VM) and Purkinje fibers (PF) and in rabbit sinoatrial (SA) node and atrium, we therefore studied the comparative effects of AM and DAM, 10(-6) M (0.68 micrograms/ml), 10(-5) M (6.8 micrograms/ml), and 5 X 10(-5) M (34 micrograms/ml), dissolved in ethanol and homologous serum. In VM, PF, and atria stimulated at 1 Hz, AM and DAM had no effect on Vmax, action potential amplitude (APA), or resting membrane potential. At 2-4 Hz, AM exerted a marked use-dependent effect in VM and PF. In atria, 5 X 10(-5) M, AM and DAM increased (p less than 0.01) action potential duration at 90% repolarization (APD90); the effective refractory period (ERP) increased by 10.5% (p less than 0.05 for AM) and 21.6% (p less than 0.01 for DAM). In VM, AM increased APD90 by 9.6% (p less than 0.01) at 10(-6) M, 13.7% (p less than 0.01) at 10(-5) M, and 16.9% (p less than 0.01) at 5 X 10(-5) M. The corresponding values for DAM were 5.6% (NS), and 7.3% (p less than 0.01), respectively. The ERP in VM was increased significantly by AM but not by DAM at all 3 drug concentrations without a change in APD90/ERP ratio. In PF, AM and DAM decreased APD50 and APD90; the effects were greater than those produced by the superfusion medium, but the degree of shortening in ERP induced by AM and DAM was not. AM and DAM (10(-5) and 5 X 10(-5) M) increased spontaneous cycle length of rabbit SA node. AM significantly decreased slope of phase 4 depolarization (10.4% at 10(-6) M, p less than 0.05; 14.5% at 10(-5) M, p less than 0.01; 24.0% at 5 X 10(-5) M, p less than 0.01). At 5 X 10(-5) M, AM significantly decreased APA, maximum diastolic potential and threshold potential with an insignificant effect on APD100.(ABSTRACT TRUNCATED AT 400 WORDS)     

胺碘酮及其活性代谢物的血浓度与临床效应相关性评价

目的探讨胺碘酮(AM)治疗心律失常的临床疗效与AM及其活性代谢物单N-去乙基胺碘酮(MDEA)血浓度间的相关性。方法住院心律失常患者37例,给予负荷量AM(600mg.d-1)达临床疗效后渐减至最小维持量(25~100)mg.d-1治疗8wk。门诊心律失常患者36例,长期服用AM(≥3mo),维持量50~200 mg.d-1。HPLC法监测AM和MDEA血浓度。结果AM、MDEA、AM MDEA和AM/MDEA值与临床效应相关系数分别为0.812 3(P>0.05)0、.703 3(P>0.05)、0.907 9(P<0.05)、0.496 9(P>0.05)。AM MDEA有效、无效和中毒浓度值分别为(1.286 0±0.745 9)(、0.636 4±0.208 6)和(2.313 0±1.682 4)mg.L-1。结论AM最小维持量为25~100mg.d-1;AM MDEA血浓度值可作为评价AM疗效,制定、修饰、调整AM治疗方案的参考指标。     

Pharmacokinetics of amiodarone,desethylamiodarone and other iodine-containing amiodarone metabolites

Summary 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 µmol/l and a maximal desethylamiodarone concentration of 3.61 µmol/l.     

The single-dose pharmacokinetics of midazolam and its primary metabolite in pediatric patients after oral and intravenous administration.

The first-dose pharmacokinetics of midazolam and its primary alpha-hydroxymetabolite were studied after single-dose administration. Eligible study patients were enrolled into one of three study arms: Arm I (midazolam/metabolite pharmacokinetic evaluation after oral administration of a syrup formulation), Arm II (the absolute bioavailability of midazolam syrup), and Arm III (midazolam and metabolite pharmacokinetics after IV administration). Complete blood sampling for pharmacokinetic analysis was available in 87 subjects. Midazolam absorption after administration of the oral syrupformulation was rapid, with adolescents absorbing the drug at approximately half the rate observed in younger children (ages 2 to < 12 years). Furthermore, midazolam t 1/2 was prolonged and CL/F reducedin adolescents as compared with younger children. Although the midazolam Vd/F appeared larger in the youngest age group after oral administration, this observation was not apparent after IV dosing, suggesting subject differences in bioavailability rather than distribution. Like midazolam, the disposition characteristics for a-hydroxymidazolam were also highly variable, with the greatest formation of metabolite (reflected by the AUC ratio) observed in children ages 2 to < 12 years. The A UC ratios of alpha-hydroxymidazolam to midazolam after IV dosing were similar across all age groups and were smaller than corresponding values following oral administration. The absolute bioavailability of midazolam averaged 36% with a very broad range (9%-71%). No relationship between midazolam bioavailability and age was observed. Overall, the disposition characteristics of midazolam and its a-hydroxy metabolite were highly variable, appeared independent of age and dose administered, and were linear over the dose range studied (0.25 to 1 mg/kg). These data suggest that an initial oral dose of 0.2 to 0.3 mg/kg should be adequateforsuccessful sedation of most pediatric patients. The inherent variability in midazolam bioavailability and metabolism underscores the importance of titrating midazolam dose to desired effect.     

Tissue distribution of amiodarone and desethylamiodarone in rats after multiple intraperitoneal administration of various amiodarone dosages

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)     

Pharmacokinetics and body distribution of amiodarone and desethylamiodarone in rats after intravenous administration

The pharmacokinetics and body distribution of amiodarone and desethylamiodarone were investigated in rats following a single intravenous dose of 100 mg/kg and 150 mg/kg of amiodarone. The decline in serum and tissue concentrations of amiodarone and desethylamiodarone are described by biexponential functions. All aspects of the typical kinetic profile of the drug and its major metabolite, desethylamiodarone, are discussed. Amiodarone is preferentially distributed in decreasing order in thyroid gland, lung, kidney, liver, heart, adipose tissue, skeletal muscle and brain. The metabolite desethylamiodarone showed a distribution pattern which is similar to that observed for the parent drug. Our study indicates an extensive distribution of amiodarone, with the thyroid gland and lung as organs with specific binding sites or uptake mechanisms and adipose tissue as a depot with a large storage capacity. We also found a very extensive distribution of the metabolite desethylamiodarone with mainly lung and thyroid gland and to some lesser extent kidney, liver and heart as organs with sites of metabolism and/or specific binding sites or uptake mechanisms and fat as a reservoir for the drug. Our data demonstrate the advantages of intravenous loading dosages of amiodarone over oral doses, since considerably higher and longer lasting effective serum and tissue concentrations of amiodarone are reached while lower quantities of the less cardio-active metabolite are formed.     

Disposition and metabolite kinetics of oral L-carnitine in humans

The pharmacokinetics of L-carnitine and its metabolites were investigated in 7 healthy subjects following the oral administration of 0, 0.5, 1, and 2 g 3 times a day for 7 days. Mean plasma concentrations of L-carnitine across an 8-hour dose interval increased significantly (P < .05) from a baseline of 54.2 +/- 9.3 microM to 80.5 +/- 12.5 microM following the 0.5-g dose; there was no further increase at higher doses. There was a significant increase (P < .001) in the renal clearance of L-carnitine indicating saturation of tubular reabsorption. Trimethylamine plasma levels increased proportionately with L-carnitine dose, but there was no change in renal clearance. A significant increase in the plasma concentrations of trimethylamine-N-oxide from baseline was evident only for the 2-g dose of L-carnitine (from 34.5 +/- 2.0 to 149 +/- 145 microM), and its renal clearance decreased with increasing dose (P < .05). There was no evidence for nonlinearity in the metabolism of trimethylamine to trimethylamine-N-oxide. In conclusion, the pharmacokinetics of oral L-carnitine display nonlinearity above a dose of 0.5 g 3 times a day.     

Response of alveolar macrophages to amiodarone and desethylamiodarone, in vitro

Administration of the antiarrhythmic drug amiodarone to humans or animals may result in lung damage. Amiodarone is metabolized to desethylamiodarone and other minor metabolites. Because amiodarone and the metabolites accumulate in the lungs, it is not possible to ascertain the role of each of these compounds in the induction of toxicity. In the present study, we utilized primary cell cultures of rat alveolar macrophages to study the actions of amiodarone and desethylamiodarone individually and in combination. Neither drug species was metabolized by the cells over 42 h in culture thereby permitting assessment of the actions of each. Both drugs induced the formation of lamellar inclusions, indicative of the development of cellular phospholipidosis. Desethylamiodarone appeared to induce formation of the structures in a shorter period of time than did amiodarone, although given adequate exposure, the two drugs produced similar responses. At shorter times of exposure and lower concentrations, desethylamiodarone was more cytotoxic than amiodarone as assessed by the release of lactate dehydrogenase. The two in combination resulted in cytotoxicity that was more than additive. The results of this study indicate that in vitro cultures of alveolar macrophages may be quite useful in studying the role these cells play in the pulmonary toxicity associated with amiodarone therapy. Additionally, this study supports the idea that a significant portion of the toxicity may result from the actions of desethylamiodarone.     

Serum and myocardial kinetics of amiodarone and its deethyl metabolite after intravenous administration in rabbits

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.     

Pulmonary fibrosis induced in the hamster by amiodarone and desethylamiodarone

Associated with amiodarone use is pneumonitis which may progress to life-threatening pulmonary fibrosis. Desethylamiodarone, a metabolite, whose role in the etiology of amiodarone-induced pulmonary toxicity has been unclear, also possesses antiarrhythmic activity and could potentially be used as an antiarrhythmic drug itself. We have used a single intratracheal administration of equimolar amounts of amiodarone or desethylamiodarone (1.83 mumol) to male golden Syrian hamsters to investigate the fibrogenicity of desethylamiodarone. Animals were terminated at 1, 7, 14, 21, and 28 days post-treatment, and toxicity was assessed by measurement of lung hydroxyproline content and by histological techniques. Amiodarone and desethylamiodarone significantly increased lung hydroxyproline content over vehicle control animals by 21 days (33 and 58% respectively). While amiodarone-treated lungs had hydroxyproline contents similar to control levels at 28 days, desethylamiodarone-treated lungs remained elevated (44% over control values). Quantitative histologic examination revealed that lungs from desethylamiodarone-treated animals displayed a greater toxic effect, while trichrome staining confirmed the increased deposition of interstitial collagen in these same animals. These results may be due to the higher affinity of the lung for desethylamiodarone and thus a prolonged exposure. The findings indicate that, in the hamster, both compounds are toxic by this route and that desethylamiodarone is not a nontoxic metabolite. Further, use of desethylamiodarone as an antiarrhythmic agent may not be devoid of the adverse effects associated with amiodarone.     

Disposition and clearance of tungsten after single-dose oral and intravenous exposure in rodents

Tungsten (W) has been nominated for study to the National Toxicology Program (NTP) because of reported associations between concentrations of W in drinking water and childhood leukemia. The disposition of W (administered as sodium tungstate dihydrate in water) in plasma, liver, kidneys, uterus, femur, and intestine of rodents (Sprague-Dawley rats and C57BL/6N mice) was characterized after exposures by oral gavage (1, 10, or 100 mg/kg) or intravenous (1 mg/kg) administration. Each tissue (or plasma) was collected and analyzed by inductively coupled plasma mass spectrometry at 1, 2, 4, or 24 h after dose administration. W was observed in plasma and all tissues after both gavage and i.v. administration. In rats, concentrations in plasma and most tissues peaked at 4 h. In mice, concentrations in plasma and most tissues peaked at 1 h. Although the amount of W in each matrix decreased significantly by 24 h, there was W remaining in several tissues, especially at the higher doses.     

Pharmacokinetics of amiodarone after intravenous and oral administration

Summary Seven patients with cardiac arrhythmias were given amiodarone 400 mg intravenously over 2 min, and 2–4 days later the same dose was given orally. The serum concentration of amiodarone was determined by HPLC; the sensitivity of the analysis was 0.1 µg/ml. The time sequence of the measurements of drug concentration made conventional compartemental analysis impossible. There was large individual variation but some of the curves suggested enterohepatic circulation. The time from oral intake to the peak serum concentration was estimated to be 7.3±2.9 h (SD). The amount of drug reaching the general circulation in 24 h after oral intake averaged 42% (22–80%). After oral administration of amiodarone 200 mg 8 hourly the serum concentration before the morning dose averaged 0.61 µg/ml after 24 h, 0.76 after 48 h, 1.18 after 1 week and 1.56 µg/ml after 1 month. In one patient, who had been on amiodarone therapy for 8 months, the drug was discontinued and the serum concentration was followed over the next 3 months. The drug elimination curve suggested an elimination half life of 13.7 days. Because of instability in physiological saline protein binding could not be precisely quantitated, but only characterized as strong. No unchanged amiodarone was found in urine. The urinary excretion of iodine over 2 h after intravenous administration suggested that 5% of orally administered amiodarone was eliminated in the urine after biotransformation. No effect of the drug was observed during the first 10 days of treatment. In 2 patients with supraventricular arrhythmia, an excellent response was seen, and in one with ventricular arrhythmia there was a good response.     

Amiodarone and desethylamiodarone concentrations in plasma and tissues of surgically treated patients on long-term oral amiodarone treatment

The tissue disposition of amiodarone and its metabolite desethylamiodarone was studied in 12 surgical patients with various types of arrhythmias after chronic oral treatment with amiodarone. Amiodarone and desethylamiodarone concentrations in plasma and tissues were determined using a simple and sensitive high performance liquid chromatographic method. The mean plasma level of amiodarone and desethylamiodarone was found to increase from 0.55 microgram/ml to 1.40 microgram/ml and 0.68 microgram/ml to 1.80 microgram/ml for the respective components following the increase of the daily oral dose from 200 mg to 600 mg of amiodarone and indicates a linear relationship between plasma concentrations and dose. The mean levels of both drugs in different parts of the heart varied for amiodarone from 15 to 48 micrograms/g and for desethylamiodarone from 48 to 71 micrograms/g, with the highest values present in the epicardially resected ventricular myocardium. The mean cardiac tissue/plasma ratios ranged for amiodarone from 12 to 35 and for desethylamiodarone from 35 to 61 and show an extensive tissue uptake in the different parts of the heart for both drugs, with the metabolite accumulation 2 to 5 times higher than the parent compound. Relatively low levels, ranging for amiodarone from 2 to 15 micrograms/g and for desethylamiodarone from 5 to 25 micrograms/g, were observed in skeletal muscle, epidermis, skin and femoral artery. By far the largest content of the drugs was found in adipose tissue with mean concentrations of 207 +/- 98 micrograms/g and 82 +/- 43 g/g respectively for the parent compound and its metabolite, which suggests that fat constitutes the main depot of the drugs.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of chlordesmethyldiazepam after single-dose oral administration in humans

The pharmacokinetics of chlordemethyldiazepam--a pharmacologically very active new 1,4-benzodiazepine derivative--in healthy subjects after administration of a single oral dose of 2 mg, was studied. Peak concentrations were reached in 1.2 +/- 0.2 hours. Plasma levels declined with a biphasic pattern, and the elimination phase had a half-life of 82.9 +/- 14.1 hours. The concentrations of the main metabolite of chlordemethyldiazepam, lorazepam, were about 7% of those of the parent compound. In urine only conjugated lorazepam could be found its 96 hour excretion reaching about 15% of the administered dose of parent drug.