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PubMed1999

Physiologically based pharmacokinetics of digoxin in mdr1a knockout mice.

To determine the contribution of the mdr1a gene product to digoxin pharmacokinetics, we constructed a physiologically based pharmacokinetic model for digoxin in mdr1a (-/-) and mdr1a (+/+) mice. After intravenous administration, total body clearance and tissue-to-plasma concentration ratios for muscle and heart were decreased in mdr1a (-/-) mice as compared with mdr1a (+/+) mice, and in particular, the digoxin concentration in the brain was 68-fold higher than that in mdr1a (+/+) mice at 12 h. On the other hand, mdr1a gene disruption did not change the contributions of renal and bile clearances to total clearance, the plasma protein binding, or the blood-to-plasma partition coefficient. Brain concentration-time profiles in mdr1a (+/+) and mdr1a (-/-) mice showed a different pattern from those in plasma and other tissues, indicating digoxin accumulation in the brain tissue. Because there was no difference in the uptake or release of digoxin by brain tissue slices from the two types of mice, we assumed the brain tissue compartment to consist of two parts (a well-stirred part with influx and efflux clearance and an accumulative part). Simulation with this model gave excellent agreement with observation when active efflux clearance across the blood-brain barrier was assumed to be zero in mdr1a (-/-) mice. The observations in other tissues in both types of mice were also well simulated.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2004

Inotropic effect of digoxin in humans: mechanistic pharmacokinetic/pharmacodynamic model based on slow receptor binding.

PURPOSE: The purpose of this study was to construct a mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for digoxin that describes the relationship between plasma concentration and inotropic response. METHODS: On the basis of results obtained in the isolated perfused rat heart, a PK/PD model for digoxin in humans was developed. In fitting the model to previously published bolus dose and concentration clamp data (shortening of electromechanical systole), the plasma concentration-time curves were used as forcing functions in the computer program ADAPT II. RESULTS: The mechanistic approach allowed a modeling of digoxin pharmacodynamics which is consistent with available inotropic response data. The estimates of the receptor binding parameters were in the same order of magnitude as those measured in vitro for ouabain. The mechanistic model explained the parameters of the empirical link model (EC50, Emax and delay time tau) in terms of the underlying processes, suggesting that the long equilibration half-time of 13 h is due to slow receptor binding. The empirical link model, in contrast, is not compatible with a noninstantaneous receptor binding process and led to estimates of the delay time tau that were dependent on the digoxin administration schedule. CONCLUSIONS: The new, mechanistic model may provide a rationale for better understanding of digoxin pharmacodynamics and could become a tool to bridge the gap between in vitro and in vivo studies.

Animals↗
PubMed2004

Effect of gentamicin on serum digoxin level in patients with congestive heart failure.

OBJECTIVE: Gentamicin is frequently used to treat infectious diseases in patients receiving digitalis therapy. The aim of this study is to evaluate the effect of gentamicin on serum digoxin level. METHOD: Twenty-four diabetic patients and patients with congestive heart failure and twelve normal healthy volunteers were enrolled in this study. The patients received digoxin treatment 0.25 mg/day. Gentamicin in a dose of 80 mg i.m. twice a day for 7 days was prescribed for these patients to treat chest infection. Serum digoxin and creatinine levels were determined before and after gentamicin administration. RESULTS: Gentamicin induced a significant increase in serum digoxin level of diabetic patients and patients with congestive heart failure. Serum creatinine level increased significantly before and after i.m. injection of gentamicin. CONCLUSION: The present study indicated that increase serum digoxin level when combined with gentamicin should be considered a risk factor for digitalis toxicity.

Adult↗
PubMed1980

Single- and multiple-dose kinetics of intravenous digoxin.

Nine healthy men received 0.5, 1.0, and 1.5 mg digoxin intravenously in random sequence on occasions separated by at least 4 wk. Digoxin concentrations were measured in serum samples drawn during 36 hr after each dose, and a mean across-dose kinetic profile was determined for each subject. After a 6-mo washout period, the same subjects received 0.25 mg digoxin intravenously every 24 hr for 10 consecutive days. Samples were drawn every 12 hr during the first 9 days and at multiple points during 72 hr after the last dose. Mean kinetic variables for the single- and multiple-dose trials were as follows: elimination half-life (t1/2), 27.9 and 38.0 hr (r = 0.62); volume of distribution, 5.5 and 7.4 l/kg (r = -0.56); total clearance, 2.50 and 2.49 ml/min/kg (r = 0.19); urinary excretion t1/2, 40.9 and 37.9 hr (r = -0.14). Mean observed and predicted predose steady-state serum concentrations were 0.59 and 0.79 ng/ml (r = -0.02). Mean values of accumulation and elimination t1/2 were nearly identical (27.8 and 27.9 hr), but were not positively correlated (r = -0.64). Multiple-dose digoxin therapy leads to no systematic change in digoxin clearance. Single-dose kinetics is poorly predictive of the rate and extent of drug accumulation and of washout kinetics during and after multiple-dose therapy.

Adult↗
PubMed1983

Influence of serum proteins on erythrocyte uptake of digoxin and digitoxin.

My purpose was to find out whether changes in serum protein content (albumin and gamma globulin) influenced erythrocyte uptake of glycosides and the capacity of erythrocytes to equilibrate glycoside levels when there are changes in protein binding. Heparinized human blood was incubated with 3H-digoxin, 6 ng/ml, and 3H-digitoxin, 44 ng/ml for 15 min. After centrifugation, distribution between plasma and erythrocytes was determined by liquid scintillation. Ratios between erythrocyte and plasma concentrations were 0.84 and 0.11 for digoxin and digitoxin. Replacing plasma by a protein-free isotonic solution led to increased erythrocyte uptake by 15% and 540% for digoxin and digitoxin. Erythrocyte uptake for both drugs was also determined in varying amounts of albumin (0 to 120 gm/l) and gamma globulin (0 to 25 gm/l). Only albumin influenced the erythrocyte uptake of these drugs. Calculations of free and bound plasma levels for both drugs showed that free digitoxin increased when albumin concentrations were equal to or less than 10 gm/l and remained constant (3%) for albumin concentrations between 15 and 120 gm/l. Free digoxin plasma levels rise when the albumin concentration is equal to or less than 15 gm/l and do not change at albumin levels between 30 and 120 gm/l. These data indicate that blood components play an important role in equilibrating changes in free digoxin and digitoxin levels.

Adult↗
PubMed1983

Interaction between digoxin and calcium antagonists and antiarrhythmic drugs.

The influence of several calcium antagonists and antiarrhythmic drugs on digoxin kinetics and actions were investigated in 36 healthy men during digoxin steady state (0.375 mg/day). The subjects were randomly assigned to three subgroups and each group received placebo (control) and two of the following regimens (doses three times a day) in a randomized sequence for 2 wk each: verapamil (80 mg) and nifedipine (10 mg), verapamil (120 mg) and gallopamil (50 mg), or propafenone (150 mg) and quinidine (250 mg). Plasma digoxin concentration (PDC) rose during the cotreatments in the sequence: gallopamil (+16%) less than propafenone (+37%) less than nifedipine (+45%) less than verapamil (almost independent of dose, +69%) less than quinidine (+118%). These increases in PDC correlated closely to decreases in renal digoxin clearances. Renal creatinine clearance was virtually unaffected. The rise of PDC resulted in increased glycoside effects, as measured by the shortening of systolic time intervals and flattening of T wave. There was a linear correlation between PDC and changes in mean corrected electromechanical systole and T wave flattening. We conclude that, in addition to quinidine, other antiarrhythmic drugs and various calcium antagonists interact kinetically with digoxin and that the increasing PDCs are cardioactive.

Adult↗
PubMed1984

The diltiazem-digoxin interaction.

To study the interaction between the calcium antagonist diltiazem and digoxin, a randomized crossover trial under steady-state conditions was carried out in 24 healthy male subjects. Diltiazem with digoxin induced an average increase of steady-state plasma digoxin concentration and AUC over 48 hr of 22.4%. This is caused by the prolongation of elimination t1/2 from 36.2 +/- 11.2 to 44.5 +/- 11.5 hr (means +/- SD) and the impairment of total digoxin clearance, dropping from 146.6 +/- 37.9 to 107.9 +/- 18.4 ml/min. Average reduction in renal clearance (from 102.1 +/- 35.5 to 85.5 +/- 42.7 ml/min) was not statistically reproducible. Apparent volume of distribution was not relevantly altered. Diltiazem kinetics did not change significantly when digoxin was concurrently given.

Adult↗
PubMed1984

Pubertal changes in net renal tubular secretion of digoxin.

To evaluate the effect of puberty on the net renal tubular secretion of digoxin, we measured the ratio of digoxin clearance to creatinine clearance in 23 patients aged 4 to 21 yr and correlated this ratio with both sexual maturity (Tanner stage) and chronologic age. All subjects were at steady-state levels for digoxin treatment; all had normal serum creatinine values for age as well as normal serum potassium levels. Mean ratio for immature children (n = 14, Tanner 1 through 3.5) was 1.45 +/- 0.66. Mean ratio for mature adolescents (n = 9, Tanner 4 through 5) was 0.95 +/- 0.28. The difference between the two groups was significant (P less than 0.05). When patients were regrouped by age using either 13 or 15 yr as a cutoff, the difference in ratios was no longer statistically significant. Based on 45 subjects (new and from our previous study) aged 2 mo to 80 yr, there was a significant decrease in the clearance ratio with increasing age, but when the 23 subjects aged 4 to 21 yr were analyzed separately, the correlation between ratio and age was not significant. It appears that the decrease in net renal tubular secretion of digoxin from childhood to adulthood correlates better with full sexual maturation at puberty (Tanner 4 through 5) than with chronologic age. This observation may represent a developmental change in pharmacokinetics with broader significance than for digoxin disposition alone.

Adolescent↗
PubMed1987

The comparative effects of verapamil and a new dihydropyridine calcium channel blocker on digoxin pharmacokinetics.

Conflicting conclusions have been reported about interaction of calcium channel blockers with digoxin. The effects of verapamil (240 mg/day) and a new dihydropyridine calcium channel blocker, isradipine (15 mg/day), on the pharmacokinetics of 1 mg intravenous digoxin were compared. All 24 volunteer subjects were healthy, male, nonobese, and aged 18 to 38 years. Groups of 12 subjects received each oral agent over 15 days, with collections of blood and urine for 72 hours after intravenous digoxin. Significant (P less than 0.05) reduction in nonrenal (7.01 +/- 1.97 to 4.00 +/- 1.86 L/hr) and total clearance (14.1 +/- 2.6 to 11.5 +/- 2.5 L/hr) were induced by verapamil, without change in renal clearance. A near-significant (P less than 0.1) increase in peripheral volume of distribution contributed to prolonged elimination half-life (23.1 +/- 4.4 to 34.3 +/- 9.7 hours). By contrast, isradipine caused only a 9% reduction in volume of distribution. Verapamil causes digoxin accumulation by reducing nonrenal elimination. No evidence of clinically relevant interaction of isradipine with digoxin was seen.

Adolescent↗
PubMed2003

Downregulation of mdr1a expression in the brain and liver during CNS inflammation alters the in vivo disposition of digoxin.

1. Inflammation is a pathophysiological event that has relevance for altered drug disposition in humans. Two functions of P-glycoprotein (P-gp) are hepatic drug elimination and prevention of drug entry into the central nervous system (CNS). Our objective was to investigate if localized CNS inflammation induced by Escherichia coli lipopolysaccharide (LPS) would modify mdr1a/P-gp expression and function in the brain and liver. 2. Our major finding was that the CNS inflammation in male rats produced a loss in the expression of mdr1a mRNA in the brain and liver that was maximal 6 h after intracranial ventricle (i.c.v.) administration of LPS. When (3)H-digoxin was used at discrete time points, as a probe for P-gp function in vivo, an increase in brain and liver (3)H-radioactivity and plasma level of parent digoxin was produced 6 and 24 h following LPS treatment compared to the saline controls. Digoxin disposition was similarly altered in mdr1a(+/+) mice but not in mdr1a(-/-) mice 24 h after administering LPS i.c.v. 3. In male rats, the biliary elimination of parent digoxin was reduced at 24 h (60%) and 48 h (40%) after LPS treatment and was blocked by the P-gp substrate cyclosporin A. An observed loss in CYP3A1/2 protein and organic anion transporting polypeptide 2 mRNA in the liver may make a minor contribution to digoxin elimination in male rats after LPS treatment. 4. Conditions which impose inflammation in the CNS produce dynamic changes in mdr1a/P-gp expression/function that may alter hepatic drug elimination and the movement of drugs between the brain and the periphery. The use of experimental models of brain inflammation may provide novel insight into the regulation of P-gp function in that organ.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2002

MDR1 genotypes do not influence the absorption of a single oral dose of 1 mg digoxin in healthy white males.

AIMS: A noncoding single nucleotide polymorphism (SNP) in exon 26 3435C > T of the highly polymorphic MDR1 gene has been demonstrated to alter digoxin absorption after induction of the MDR1 gene product P-glycoprotein by rifampicin or after multiple oral dosing. The aim of the study was to investigate the effects of the major known MDR1 SNPs on the absorption of digoxin after a single oral dose in a large sample without drug pretreatment. METHODS: Fifty healthy white male subjects between the age of 18 and 40 years were enrolled. Following an overnight fast, all subjects received a single oral dose of 1 mg digoxin. Venous blood samples were taken at intervals up to 4 h post dose to obtain a pharmacokinetic profile. RESULTS: AUC(0,4 h), Cmax and tmax, used as indices of digoxin absorption, were not significantly different in any of the genotype groups tested. In particular, there was no significant difference between homozygous carriers of the C and T allele in exon 26 3435 (AUC(0,4 h) 9.24 and 9.38 micro g l-1 h, Cmax 4.73 and 3.81 micro g l-1, tmax 0,83 and 01.14 h). CONCLUSIONS: This lack of effect of the major MDR1 SNPs on digoxin absorption might be explained by saturation of the maximum transport capacity of intestinal Pgp at the dose used.

Absorption↗
PubMed2003

Voriconazole does not affect the steady-state pharmacokinetics of digoxin.

AIMS: Voriconazole is a triazole antifungal agent with potent fungicidal activity against Aspergillus species. Digoxin is a commonly prescribed cardiac glycoside with a narrow therapeutic index. This aim of this study was to investigate the effect of multiple-dose voriconazole on the steady-state pharmacokinetics of digoxin in healthy male volunteers. METHODS: This was a double-blind, randomized, placebo-controlled, parallel-group study. All subjects received daily administration of oral digoxin for a total of 22 days (0.5 mg twice daily on day 1, 0.25 mg twice daily on day 2 and 0.25 mg once daily on days 3-22). In addition, on days 11-22 the subjects were randomized to receive either voriconazole (200 mg twice daily) or matching placebo. RESULTS: Concomitant administration with voriconazole did not significantly alter the Cmax, AUCtau, tmax or CLR of digoxin at steady state. The ratios between groups for Cmax and AUCtau at day 22, corrected for baseline (day 10) were 109.8%[90% confidence interval (CI) 97.1, 124.1] and 100.5% (90% CI 91.4, 110.5), respectively. In addition, group mean Cmin values were similar in both treatment groups throughout the study. There were no significant differences between treatments with respect to the incidence of adverse events, all of which were classified as mild and transient in nature. CONCLUSIONS: The steady-state pharmacokinetics of digoxin are not affected in a clinically relevant manner by the concomitant administration of voriconazole.

Administration, Oral↗
PubMed1998

Effects of digoxin and digitoxin on circadian blood pressure profile in healthy volunteers.

BACKGROUND: The aim of the study was to investigate the potential effects of chronic digoxin or digitoxin treatment or circadian blood pressure profile in normotensive subjects. METHODS: In two randomized double-blind, placebo-controlled cross-over protocols, 22 healthy normotensive subjects were enrolled, 12 subjects in either study. After adequate loading doses, digoxin 0.25 mg twice daily or digitoxin 0.1 mg daily was given for a total of 10 days. Automatic 24-h ambulatory blood pressure measurements were carried out at days 4 and 10 of either glycoside or placebo. RESULTS: Digoxin treatment significantly decreased heart rate (HR) and diastolic blood pressure (DBP) during the overnight sleeping phase of day 10 compared with placebo (HR, 4 beats min-1; DBP, 8 mmHg; P < 0.05). Digitoxin treatment significantly decreased heart rate and diastolic blood pressure during the overnight sleeping phase of day 4 (HR, 8 beats min-1; DBP, 7 mmHg) and day 10 (HR, 7 beats min-1; DBP, 5 mmHg) compared with placebo (P < 0.05). Neither digoxin nor digitoxin significantly affected systolic blood pressure. CONCLUSIONS: Both digoxin and digitoxin, within therapeutic steady-state plasma concentrations, reduced diastolic blood pressure and heart rate during overnight sleep, presumably because of increased parasympathetic activity or decreased sympathetic activity.

Adult↗
PubMed2002

Functional changes in isolated guinea-pig papillary muscle induced by monensin and digoxin.

The effects of digoxin and monensin on contraction force (CF), initial contraction velocity (ICV), average contraction velocity (ACV), initial relaxation velocity (IRV) and stimulus to response time (ST) in 'fatigued' (tired) and 'non-fatigued' (fresh) guinea-pig papillary muscles were investigated. 'Fatigued' muscles had lost 30% of their original CF with the elapse of time before they were treated. The 5 h of measurement were divided into five periods (T0 was equilibration, T1, T2, T3 and T4 were, respectively, 1, 2, 3 and 4 h after drug administration). It was found that both monensin and digoxin increased the CF, ICV and ACV at T1 and increased the IRV at T2. Digoxin lost its effect with the elapse of time while monensin did not. Digoxin also decreased the ST at T2, T3 and T4. However, monensin did not change the ST. It was also found that 'fatigued' and 'non-fatigued' guinea-pig papillary muscles did not respond to the drug treatment differently. It was concluded that the initial effects of these two drugs on guinea-pig papillary muscles are similar regarding contractility but in time digoxin loses its effect while monensin does not.

Animals↗
PubMed2002

The effect of digoxin on the electrocardiogram of healthy middle-aged and elderly patients at rest and during exercise--a comparison with the ECG reaction induced by myocardial ischemia.

The effect of digoxin on electrocardiogram (ECG) at rest and during exercise, and on QRS amplitude variability (variance ECG) was studied in 20 healthy, middle-aged men and women. Exercise test and variance ECG were performed before and after pretreatment with digoxin orally. Plots of ST-segment level vergus heart rate (HR) were constructed from the rest and exercise ECG recordings. Thus obtained ST/HR loops were compared with loops from 10 male patients with angiographically verified ischemic heart disease (IHD). Pretreatment with digoxin caused a significant (P <.001) ST depression in precordial leads, which was similar in men and women and returned promptly to the isoelectric level after exercise resulting in a counterclockwise rotation of the ST/HR loop. In IHD patients, the exercise-induced ST-segment depression was significantly more pronounced (P <.01) and the ST-segment recovery slower, resulting in clockwise rotated ST/HR loops. The results of variance ECG were not influenced by digoxin. The digoxin-induced ST-reaction during exercise mimics exercise-induced ischemic ST-reaction in patients with IHD, but can still be discerned by the analysis of ST/HR loops.

Administration, Oral↗
PubMed1976

[Influence of antacids on plasma concentration of digoxin in man (author's transl)].

In a cross-over trial the plasma concentrations of digoxin have been studied in nine healthy subjects given oral doses of digoxin alone and simultaneoulsy with magnesium-aluminium-silicate-hydrate and dimagnesium-aluminium-trisilicate. The administration of 0.75 mg digoxin on each of 3 days and 0.375 mg on each of 2 days caused a 17 percent decrease of digoxin plasma level when given simultaneously with 1100 mg magnesium-aluminium-silicate-hydrate (n=4) and a 24 percent increase when given with 1000 mg dimagnesium-aluminium-trisilicate (n=5), respectively. The differences are not significant. The experiments suggested that antacids containing magnesium-aluminium-silicate do not impair the absorption of digoxin in man.

Administration, Oral↗
PubMed1977

[Plasma-digoxin concentration in patients at time of hospital admission (author's transl)].

Plasma-digoxin and serum creatinine concentrations were determined on admission in 145 unselected patients previously digitalized as outpatients. Adequate digitalization was found in 62.7%, inadequate doses in 15.9% of patients. In the latter group the daily dosage reported by the patients failed to correlate with the plasma-digoxin concentration by radioimmunoassay. One-fifth of all patients had clinical evidence of digitalis intoxication. Of these, 69% had plasma-digoxin concentrations of more than 2.0 ng/ml and 31% less than 2.0 ng/ml. Mean digoxin concentration for all patients with signs of digitalis intoxication was 2.5+/-0.9 ng/ml. In patients simultaneously receiving spironolactone or canrenoate-K+ there was danger of falsely high values for digoxin because of interference of those drugs with the radioimmunoassay.

Ambulatory Care↗
PubMed1992

[Severe digitalis poisoning after the ingestion of 1 g of digoxin].

A 50-year-old, previously healthy, woman swallowed 1 g digoxin powder, dissolved in water, with suicidal intent. On admission to hospital one hour later, having vomited three times at home, the prominent signs were somnolence and hypersalivation. Serum digoxin level was 3.37 ng/ml. There followed repeated episodes of asystole alternating with ventricular fibrillation requiring cardiopulmonary resuscitation over 90 min and adrenaline administration. Repeated electrical defibrillation, administration of dopamine, phenytoin and lidocaine, as well as transitory transvenous electrical stimulation became necessary. Anti-digoxin antibody fragments were administered, initially 80 mg, to a total of 3,280 mg over 24 hours. After 3 days of intensive care and a further 21 days in hospital she was discharged and referred to psychiatric treatment. This case demonstrates that even severe digoxin poisoning can be successfully treated without sequelae by the appropriate administration of digoxin antidote. The main problems in this case were regulation of the dosage and acquiring the necessary amount of antidote which greatly exceeded the hospital's own depot.

Acute Disease↗