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PubMed1983

Effect of quinidine on digoxin distribution and elimination in guinea pigs.

The effect of quinidine on the distribution and elimination of digoxin was examined by comparing the change in the steady-state volume of distribution (Vdss), determined both from in vivo plasma elimination and tissue distribution and in vitro serum binding studies, with that in the total body clearance (CLtot) determined from biliary, renal, and metabolic clearances in guinea pigs. The plasma disappearance of digoxin after a 250-micrograms/kg iv dose followed a triexponential decline in both the control and quinidine-treated guinea pigs. In the quinidine-treated guinea pigs, the pharmacokinetic parameters Vdss and CLtot significantly decreased to approximately half of that for the control guinea pigs. The tissue-to-plasma partition coefficients (Kp) of all tissues studied, i.e. liver, heart, muscle, and brain, at 6 hr after bolus injection of digoxin decreased in the presence of quinidine. The serum free fraction and the plasma-to-blood concentration ratio of digoxin in the therapeutic range did not show a significant alteration in the presence of quinidine. This suggested that the decrease of Kp is due mainly to the inhibition of tissue distribution of digoxin by quinidine. The biliary clearance (CLB) and renal clearance (CLR) also significantly decreased in the presence of quinidine. It was concluded that quinidine caused a inhibition of digoxin in the tissue binding or uptake, which significantly decreased the Kp values of digoxin; this result may explain the significant decrease of Vdss. Moreover quinidine may be the cause of a reduction of biliary, renal, and metabolic clearances, which significantly decrease the CLtot of digoxin.

Animals↗
PubMed1986

Comparative in vivo evaluation of a radioimmunoassay and a chromatographic assay for the measurement of digoxin in biological fluids.

The concentrations of digoxin in plasma and urine samples obtained from three healthy male volunteers, who received 1.2 mg of labeled digoxin perorally and intravenously, were simultaneously measured by a commercially available radioimmunoassay (RIA) and by a combined column thin-layer chromatographic assay (CA). The CA method, previously shown to assay digoxin specifically, was also used to monitor the individual digoxin metabolites. The results of this investigation showed that digoxin was significantly metabolized, particularly after peroral administration. The lower level of sensitivity of the RIA in plasma was 0.4 ng/mL. There were highly significant positive linear correlations between the values of the following parameters of digoxin as obtained by the RIA and CA methods: the concentrations in plasma and urine, the AUCs, and the cumulatively excreted amounts in urine. The two assays did not give completely identical results either with plasma or urine; the slopes of the regression lines deviated from unity in a significant number of cases. However, there was no relationship between the magnitude of the slopes of the regression lines and the extent of metabolism. It was concluded that the commercially available RIA evaluated was specific for digoxin and that the presence of digoxin metabolites did not affect the determinations.

Biotransformation↗
PubMed1999

P-glycoprotein system as a determinant of drug interactions: the case of digoxin-verapamil.

Digoxin, which has a very narrow therapeutic window, is one of the most commonly prescribed drugs in the treatment of congestive heart failure. In some cases of atrial fibrillation digoxin is used in combination with verapamil. Verapamil can increase the plasma concentration of digoxin up to 60-90%. So far the precise mechanism of this pharmacokinetic drug-drug interaction is not known. Many studies suggest that verapamil reduces the renal clearance of digoxin. The energy-dependent membrane-bound transport enzyme, P-glycoprotein, may also be involved. Reports from oncology research show that verapamil can interact with P-glycoprotein as a modulator. Also taking into account that digoxin, like many anticancer drugs, is a substrate for P-glycoprotein, it is likely that P-glycoprotein modulation accounts for the digoxin-verapamil interaction. Current knowledge suggest that the non-competitive digoxin-verapamil interaction is due to inhibition of P-glycoprotein activity by verapamil resulting in a decreased renal tubular elimination of digoxin.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1988

Digoxin, magnesium, and potassium levels in a forensic autopsy material of sudden death from ischemic heart disease.

In 91 cases where the cause of death was heart disease, digoxin, Mg and K concentrations in serum and ventricular myocardium were measured post mortem. Forty per cent were positive for digoxin in both serum and myocardium. The mean serum level was 5.1 +/- 2.4 nmol/l and the mean myocardial level was 42.6 +/- 27.5 ng/g. Correlation could be established between serum and myocardial concentrations of digoxin. There were statistically significant differences in serum as well as in myocardial digoxin levels in persons on 0.13 mg and 0.25 mg per day, respectively. Myocardial levels of Mg and K were low as generally found in persons with ischemic heart disease. There was no correlation between these levels and myocardial digoxin concentrations. Caution must be exercised in the assessment of digoxin results from cadaver samples because of the postmortem rise of digoxin serum concentrations. Considering this fact, the results still indicate that the prevalence of toxic digoxin concentrations might be more common than previously thought.

Adult↗
PubMed1984

Physical exercise and binding of digoxin to skeletal muscle--effect of muscle activation frequency.

Ten healthy subjects who had ingested 0.5 mg digoxin daily for at least 10 days, performed a 1-hour bicycle exercise test on two occasions, 24 h after the latest dose, with the same work load but at two different pedalling rates, 40 and 80 rpm. During exercise the mean digoxin concentration in the thigh muscle increased by 8% at 40 rpm (n.s.) and by 29% at 80 rpm (p less than 0.01). The serum digoxin concentration decreased by 39% at both pedalling rates (p less than 0.001). The results suggest that the increase in skeletal muscle digoxin concentration during exercise is related to the neuromuscular activation frequency. The digoxin concentration in erythrocytes was measured in 16 healthy subjects before and 1 minute after a 1-hour bicycle exercise test. The erythrocyte digoxin concentration decreased by 12% (p less than 0.01) during the exercise indicating that the increased uptake of digoxin in skeletal muscle during exercise influences the digoxin concentration in other tissues.

Adult↗
PubMed1989

Effect of urapidil on steady-state serum digoxin concentration in healthy subjects.

In an open, randomized, two-period change-over study the effect of urapidil, an antihypertensive agent, on steady-state serum digoxin levels was investigated in 12 healthy male volunteers. The subjects were given digoxin 0.25 mg once daily for 4 days to produce a steady-state digoxin level in serum. At the end of that time the subjects received either digoxin monotherapy or digoxin and concomitant treatment with urapidil 60 mg b.d. for a further 4 days. Subsequently the treatments were changed over. The absorption characteristics Cmax and tmax of digoxin were not altered by concomitant urapidil treatment. The geometric mean and nonparametric 95% confidence limits of digoxin relative bioavailability were 97% (93%-103%). Therefore, concomitant administration of urapidil with digoxin treatments did not appear to alter the rate and extent of absorption of the glycoside.

Adult↗
PubMed1986

The comparative cardiovascular effects of digoxin and food alone and in combination in normal males.

The effects of the ingestion of food and digoxin on the cardiovascular system alone and in combination have been observed in eight healthy subjects. A positive inotropic response was seen following food (2.5 MJ) and intravenous digoxin (0.01 mg/kg) with significant decreases in QS2Index (QS2I) pre-ejection period (PEP) and PEP/LVET (LVET - left ventricular ejection time). These responses were potentiated when food and digoxin were combined. Opposing effects of food and digoxin on % diastole (%D) and diastolic time were observed, food decreasing %D and DT while digoxin increased these variables. Both food and digoxin decreased T-wave amplitude, and digoxin alone or in combination with food decreased QTc. The positive inotropic effect of a 2.5 MJ mixed meal and a loading dose of digoxin in healthy subjects are of similar degree, different mechanism, and are potentiated in combination.

Adult↗
PubMed1979

Pharmacokinetics of digoxin: relationship between response intensity and predicted compartmental drug levels in man.

A study designed to investigate the relationship between the pharmacokinetics of digoxin and a measure of its pharmacological effect has been conducted. Serum digoxin concentrations and systolic time intervals were measured concurrently in 12 normal male volunteers following a 1.0 mg i.v. bolus injection. The averaged serum digoxin concentration--time and response--time data were analyzed pharmacokinetically using a three-compartment open model and nonlinear least-squares fitting. When only the serum level--time data were analyzed, a close relationship was found between calculated digoxin levels in the slowly distributing (deep) peripheral compartment and response of the heart to digoxin, as measured by changes in the QS2 index (delta QS2I). Although it was not possible to distinguish clearly a linear from a nonlinear relationship between digoxin levels in the deep compartment and delta QS2I, the nonlinear relationship gave the best overall fit when both serum digoxin and delta QS2I data were fitted simultaneously. The simultaneous fit yielded a total body clearance of digoxin of 3.6 ml/min/kg and a terminal t1/2 of 42 hr.

Digoxin↗
PubMed1976

Serum digoxin concentration and half-life in newborn.

Serum digoxin concentration and half-life were radioimmunologically determined in 9 mature newborns after 7 days medication with digoxin. The newborns were in respiratory distress treated with continuous positive airway pressure or were suspected to have serious congenital heart disease. Loading dose was 26 mug/kg body weight intravenously and 35 mug/kg body weight orally, respectively. Maintenance dose corresponded to 1/8th of the digitalization dose twice daily. The serum digoxin level 12 h after the last dose varied between 1.4 and 2.5 ng/ml (mean 2.0 ng/ml, Sx=0.4). The serum half-life of digoxin varied between 21.7 and 42.4 h (mean 30.0 h, Sx=7.7). The mean serum half-life of digoxin of 30 h attained values found in adults without renal disease. This suggests that the serum digoxin levels of newborns which are usually higher if compared with those of adults result from higher digoxin doses per unit body weight and not from diminished digoxin elimination.

Digoxin↗
PubMed1978

[Plasma concentrations of digoxin in patients under intensive care conditions and in patients undergoing anesthesia and operation (author' transl)].

Pharmacokinetic behavior of digoxin or beta-acetyldigoxin was examined in 66 patients (27 patiets under intensive care conditions, partially with controlled breathing, 22 patients undergoing extirpation of the uterus and 17 patients treated with radium or chemotherapeutics; 19 males and 47 females) by determining plasma concentrations of digoxin (PDC). After intravenous and oral application with a maintenance dose of 0.20--0.50 mg/day blood was taken daily during a 2 to 3 week period, resulting in 510 determinations. 24 hours after the first application of 0.50 mg digoxin i.v. the mean values of PDC amounted to 0.62 +/- 0.08 ng/ml. After 0.40 or 0.25 mg digoxin per day i.v. therapeutical concentrations could be observed at the third vs fifth day. An equilibrium of PDC was reached on the 6th day after starting digitalization using maintenance doses. Intravenous application of 0.25, 0.40 or 0.50 mg digoxin per day resulted in a mean steady state of 0.68 +/- 0.37, 0.86 +/- 0.33 or 1.27 +/- 0.49 ng/ml PDC, respectively. The results were significantly different (p less than 0.01--0.001). Serial measurements indicated a great variation of PDC. In patients without renal failure the intraindividual variation of the plasma concentrations was maximal 37.4% referring to the mean steady state, interindividual 37.1% and the evaluation of the inter- and intraindividual differences amounted to 54.1%. After oral administration of digoxin (maintenance dose: 0.50 mg/day) or beta-acetyldigoxin (maintenance doses: 0.20--0.40 mg/day) differences in PDC of 38.3% and 29.7% were obtained. Body weight, age and serum creatinine concentration were partly responsible for the variance of PDC. Multiple linear regression between stead state PDC and dose, age, body weight and serum creatinine concentration revealed 62.1% of the variance of the PDC after intravenous administration of digoxin. After oral administration of beta-acetyldigoxin 39.9% were obtained. Thus, 40% of the variance were caused by differences in distribution and elimination of digoxin after i.v. application. After oral application additional 20% of the variance could be attributed to resorption and possible disturbances.

Cardiac Glycosides↗
PubMed1993

Basic evaluation of 67Ga labeled digoxin derivative as a metal-labeled bifunctional radiopharmaceutical.

To develop metal-labeled digoxin radiopharmaceuticals with affinity with anti-digoxin antibody as well as Na+,K(+)-ATPase, a digoxin derivative conjugated with deferoxamine was synthesized. The derivative had a high binding affinity with 67Ga at deferoxamine introduced to the terminal sugar ring of digoxin. The 67Ga labeled digoxin derivative showed enough in vitro binding affinity and selectivity to anti-digoxin antibody as well as Na+,K(+)-ATPase. The 67Ga labeled digoxin derivative is considered to be a potential metal-labeled bifunctional radiopharmaceutical for digoxin RIA as well as myocardial Na+,K(+)-ATPase imaging.

Cross-Linking Reagents↗
PubMedDate not supplied

Pharmacokinetic and pharmacodynamic aspects of concomitant mibefradil-digoxin therapy at therapeutic doses.

This study investigated the effect of mibefradil on digoxin pharmacokinetics an pharmacodynamics. Following a loading dose of digoxin (0.375 mg, three times, day 1), 0.375 mg was administered once daily to 40 healthy subjects (days 2-15). Mibefradil was administered daily at 50 mg, 100 mg, or 150 mg (days 9-15). With co-administration of 50 mg or 100 mg mibefradil (the recommended doses), mean digoxin Cmax values increased 1.19- and 1.32-fold, respectively; Cmin values were 0.95- and 1.04-fold, respectively; mean AUC0-24 h increased 1.05- and 1.11-fold, respectively; and the total amount of digoxin excreted in urine remained unchanged. Digoxin monotherapy produced modest but transient prolongations of PQ interval, small decreases in heart rate, and no changes in blood pressure. With the addition of mibefradil, no effects on trough blood pressure or cardiac index were observed, but there was a further increase in PQ interval and decrease in heart rate. In a previous study, mibefradil had no significant effect on trough plasma digoxin concentration in patients with congestive heart failure and ischemia. Therefore, while the vast majority of patients should not need their digoxin dosages adjusted when given mibefradil, an occasional patient may require dose reductions based on clinical response and plasma digoxin.

Adult↗
PubMed1990

Total digoxin-like immunoreactive factor(s) in healthy population, uncomplicated term pregnancies and neonates.

Free digoxin-like immunoreactive factor(s) (DLIF) which may have a homeostatic role, as documented in different physiological conditions, but is generally undetectable in plasma from normal population. Total digoxin-like immunoreactive factor(s) (protein bound and free) can be estimated after plasma is heated. In this study, total digoxin-like immunoreactive factor(s) as measured in plasma in a well defined control population and compared to healthy term pregnant women and neonates, categories known to be associated with increased free digoxin-like immunoreactive factor(s) concentrations. The mean level of this factor(s) in the control group was 706 +/- 129 pg digoxin equivalent/ml (pg/ml) and was unaffected by age and sex. Significantly increased levels of total digoxin-like immunoreactive factor(s) were found in pregnant women and neonates (928 +/- 127 and 1242 +/- 367 pg/ml, respectively). We conclude that levels of total digoxin-like immunoreactive factor(s) are increased in term pregnancies and neonates, similarly to its free form. However total digoxin-like immunoreactive factor(s) is detected in the normal population as a plasma component, contrary to its free form, which is generally undetectable.

Adult↗
PubMed1984

The effect of nifedipine on serum digoxin concentrations in patients.

Drug interactions with digoxin are being increasingly recognized. Some calcium antagonists have been shown to alter digoxin kinetics and changes in digoxin dosage have been recommended. To determine whether nifedipine affects serum digoxin concentrations in patients during combined drug administration, serum digoxin concentrations were determined before and during concomitant drug administration in 14 cardiac patients. The mean (+/- SD) digoxin concentration was 0.92 +/- 0.5 ng/ml before and 0.96 +/- 0.5 ng/ml after 4 days of nifedipine therapy in eight inpatients. For the group of 14 patients, the mean level was 0.78 +/- 0.4 ng/ml before nifedipine and 0.8 +/- 0.4 ng/ml after 1 week of combined drug administration, and 0.84 +/- 0.5 ng/ml after 2 weeks of combined drug administration. These data suggest that nifedipine does not significantly alter serum digoxin concentrations in cardiac patients receiving combined digoxin and nifedipine in the clinical setting.

Aged↗
PubMed1986

Serum digoxin concentrations during ethmozine antiarrhythmic therapy.

The potential for pharmacokinetic drug interaction between ethmozine (moricizine HCl), a phenothiazine class I antiarrhythmic investigational drug, and digoxin was evaluated in 13 cardiac patients with normal renal function. Antiarrhythmic therapy was initiated in patients with potentially lethal (nonlife-threatening) ventricular arrhythmias (greater than 30 ventricular ectopic beats [VEB]/hr) who were receiving maintenance digoxin therapy for congestive heart failure and/or atrial fibrillation. Serum digoxin concentrations of patients were measured frequently by radioimmunoassay and plasma ethmozine concentrations by high-performance liquid chromatographic methods. Patients entered a short-term (4 weeks) single-blind, placebo controlled ethmozine protocol with an option to receive long-term (1 to 6 months) open-label maintenance ethmozine therapy. Ambulatory ECGs (48 hour) used to assess antiarrhythmic efficacy of ethmozine during each week of the short-term protocol showed that 77% of patients demonstrated greater than 90% mean hourly frequency suppression of all forms of ventricular ectopy. Serum digoxin concentrations during short-term ethmozine dosing showed a nonsignificant (p greater than 0.05) increase of 10% to 15% (mean 0.91 ng/ml to 1.13 ng/ml). The short-term protocol serum digoxin levels correlated closely with serum digoxin concentrations during placebo therapy (1st week, r = 0.90; 2nd week, r = 0.87). Serum digoxin concentrations were not significantly different (p greater than 0.05) from placebo values at the end of 1, 3, and 6 months of maintenance ethmozine therapy. Thus, we conclude that ethmozine administered in an antiarrhythmic efficacious dosage (10 mg/kg/day) showed no important clinical or statistically significant change in serum digoxin concentrations of cardiac patients with normal renal function.

Adult↗
PubMed1988

Increase in experimental infarct size with digoxin in a canine model of myocardial ischemia-reperfusion injury.

In the present study, dogs were pretreated with intravenous digoxin, 0.0125 mg/kg/day, for 6 to 7 consecutive days to achieve clinically relevant serum concentrations; untreated animals were used as control subjects. After pretreatment, nine digoxin-pretreated dogs and nine control dogs were anesthetized and subjected to a 60-minute occlusion of the left circumflex coronary artery, followed by 6 hours of reperfusion. Anatomic myocardial infarct size, expressed as a percentage of the areas at risk of infarction and as a percentage of the total left ventricle were: 20.2 +/- 3.3% control vs 35.4 +/- 6.2% digoxin-pretreated (p less than 0.05) and 8.6 +/- 1.3% control vs 14.7 +/- 2.5% digoxin-pretreated (p less than 0.05), respectively (2.04 +/- 0.37 ng/ml serum digoxin). Regional myocardial blood flow in the nonischemic and ischemic zones tended to be lower in digoxin-pretreated than in control animals at baseline testing and were significantly reduced in the anterior subendocardial sites of digoxin-pretreated dogs during ischemia and reperfusion. These data suggest that an exacerbation or enhancement of myocardial ischemia-reperfusion injury may occur in the presence of clinically observable serum digoxin concentrations.

Animals↗
PubMed1989

Clinical value of serum digoxin assays in outpatients: improvement by the standardization of blood sampling.

Everyday physical activity previously has been shown to affect serum digoxin concentrations. Standardized rest in the supine position increases outpatient serum digoxin levels 0% to 75%. The present study comprising 56 outpatients treated with digoxin was undertaken to elucidate the clinical importance of a standardized period of rest before collection of the blood sample. Blood samples were taken about 24 hours after the latest dose, before and after 2 hours of rest in the supine position. A careful clinical examination, including electrocardiogram (ECG) findings, systolic time intervals, and chest x-ray studies, was performed to identify adverse effects/intoxication or failure of digitalis treatment. Signs of failure of digitalis treatment occurred in 12% of the patients, with a serum digoxin concentration of 0.68 +/- 0.15 (mean +/- SD) nmol/L before rest and 0.85 +/- 0.22 nmol/L after rest. Eleven percent showed signs of adverse effects/intoxication, with serum digoxin concentrations of 1.70 +/- 0.70 nmol/L before rest and 2.08 +/- 0.80 nmol/L after rest. The serum digoxin concentrations of the adequately treated patients (77%) were 1.02 +/- 0.35 nmol/L before rest and 1.28 +/- 0.41 nmol/L after rest. The importance of standardized rest before blood sampling is illustrated by the fact that only one third of the patients without signs of adverse effects/intoxication or failure of digitalis treatment had serum digoxin concentrations within the therapeutic range most commonly used (1.2 to 2.6 nmol/L) without supine rest. If allowed to rest in the supine position before blood sampling, approximately 60% of the adequately treated patients had serum digoxin concentrations within this range.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1975

Dose-response relation between therapeutic levels of serum digoxin and systolic time intervals.

A dose-response relation between cardiac glycosides and systolic time intervals has previously been established in short-term studies in which the glycoside was administered intravenously in these studies there was uncertainty regarding the steady state kinetics, and maintenance of the early serum levels would have resulted in toxicity. Accordingly, we studied the effect on systolic time intervals of small increments of serum digoxin within the therapeutic range. Serum digoxin concentration and systolic time intervals were measured in 21 patients receiving 0.25 mg of the glycoside daily. The daily dose was increased to 0.5 mg and measurements were repeated 5 to 7 days later. Serum digoxin concentration with the smaller dose was 0.56 plus or minus (standard error) 0.06 ng/ml and increased to 1.18 plus or minus 0.11 ng/ml with the larger dose. Associated with the increased serum digoxin was a mean decrease in duration of total electromechanical events of 6.3 plus or minus 2.9 msec (P smaller than 0.025), which resulted from a mean shortening of left ventricular ejection time of 5.6 plus or minus 3.0 msec (P smaller than 0.05). The mean decrease in preejection phase of 1.1 plus or minus 2.1 msec was insignificant (P larger than 0.2). Repeated measurements in control patients showed no change in serum digoxin concentration or systolic time intervals. In nine patients the digoxin dose was randomly varied between 0 and 0.75 mg and measurements were made 4 to 5 days after drug administration at each dose level. The correlation coefficient between changes in serum digoxin and changes in left ventricular ejection time was minus 0.55 (P smaller than 0.01) the data indicated that increasing the maintenance dose of digoxin while keeping the serum level within therapeutic range will result in improved ventricular function as assessed by determination of systolic time intervals.

Adult↗