Renal Excretion Of Digoxin Research Articles

Digoxin toxicity and ritonavir

P-glycoprotein is an MDR1 gene product that functions as an ATP-dependent drug efflux pump. P-glycoprotein is expressed in the apical membrane of epithelial and endothelial cells of a number of tissues, including the liver, small intestines, kidney and the blood–brain barrier, where it results in reduced absorption, enhanced elimination and the prevention of drug entry into the central nervous system, respectively. Digoxin is a substrate for p-glycoprotein, and given its low therapeutic index its concurrent use with drugs that have a propensity to increase digoxin exposure is of significant concern. Clinically significant drug interactions with digoxin have been associated with itraconazole, quinidine, clarithromycin and verapamil that inhibit intestinal or renal digoxin excretion by inhibiting p-glycoprotein-mediated transport [1]. All protease inhibitors are substrates for p-glycoprotein [2]. The predominant effect of ritonavir on p-glycoprotein expression has been somewhat controversial [3]. A recent pharmacokinetic study in normal volunteers [4] showed that ritonavir decreased the renal clearance of digoxin. It is plausible that the mechanism of this is through the inhibition of p-glycoprotein-mediated transport in the renal proximal tubules. We describe a case of digoxin toxicity, which we believe was precipitated by the introduction of ritonavir. A 61-year-old woman presented to the emergency department with increasing nausea and vomiting 3 days after the addition of ritonavir 200 mg twice a day to lamivudine, indinavir and stavudine. Before this she had been tolerating indinavir 800 mg three times a day, lamivudine 150 mg twice a day and stavudine 40 mg twice a day for the past 3 years. She had been diagnosed as being HIV infected in 1995 after her husband died from AIDS-related complications. The past history was significant for rheumatic heart disease, with valve replacement and permanent pacemaker insertion in 1992. She had been taking a stable dose of digoxin (0.250 mg a day) since developing atrial fibrillation after open-heart surgery 8 years earlier. Other concurrent medications at the time of admission included digoxin, coumadin 5 mg alternating with 10 mg a day and aerosolized pentamidine once a month. The basic laboratory work-up on admission was normal apart from an unconjugated bilirubin level of 129 μmol/l, which was up from 30 μmol/l, probably explained by the increased exposure to indinavir after the introduction of ritonavir. The electrocardiogram showed a paced rhythm. The digoxin level on admission, measured by the CEDIA immunoassay (Roche Diagnostic Systems Inc., Branchburg, NJ, USA), approximately 5 h after her last dose was 7.2 nmol/l (N 1–2.6). Digoxin levels were repeated in duplicate using the Immono1System (Bayer Diagnostics, New York, USA) to rule out any interference with bilirubin. Levels 11, 15 and 27 h after the last dose were 5.5, 4.5 and 2.7 nmol/l. By the second day in hospital she was clinically much improved. Digoxin was permanently discontinued without any sequelae. The original antiretroviral drugs (lamivudine, indinavir and stavudine) were restarted without significant side-effects. The inhibition of p-glycoprotein-mediated transport by ritonavir may be one mechanism to explain digoxin toxicity in this woman previously on a stable dose of digoxin for several years. A more recent study suggested that ritonavir may be unique among protease inhibitors in its inhibition of p-glycoprotein, and that this may occur in particular at the level of the renal tubules. Although p-glycoprotein is often co-expressed with cytochrome P450 3A4, this case appears to represent drug interaction mediated through p-glycoprotein because digoxin is a substrate for p-glycoprotein but not cytochrome P450 3A4. Of interest is the fact that the patient described had been on a stable dose of indinavir for 3 years without any evidence of toxicity. This is in support of in-vitro data, which suggest that indinavir is not a significant inhibitor of p-glycoprotein-mediated transport. As the HIV population ages the potential for these types of drug interactions will increase with more exposure to drugs such as digoxin. Other factors such as genetic polymorphisms in MDR1 may be important in predicting the likelihood of a clinically significant drug interaction as outlined in a recent study of pharmacokinetic interactions between clarithromycin and digoxin [3,5]. Our case and pharmacokinetic data support the fact that patients who are concurrently treated with ritonavir and digoxin may be at risk of digoxin toxicity and should be closely monitored.

The Effect of Erythromycin and Clarithromycin on the Pharmacokinetics of Intravenous Digoxin in Healthy Volunteers

Several case reports have suggested an interaction between digoxin and macrolide antibiotics. The authors investigated the effect of erythromycin and clarithromycin on the pharmacokinetics of intravenously administered digoxin (0.5 mg) in healthy subjects. Nine male subjects participated in three studies (digoxin alone, digoxin with erythromycin, and digoxin with clarithromycin). Subjects took erythromycin (800 mg per day) or clarithromycin (400 mg per day) on the day before digoxin dosing and during the kinetic study. Neither of the macrolides affected serum digoxin concentration‐time curves. However, more than 1.3‐fold increases in urinary digoxin excretions were observed during erythromycin and clarithromycin coadministration compared with digoxin alone. There were significant differences in renal clearance between macrolide coadministration and the control condition (digoxin alone: 98.4 ml/min; digoxin with erythromycin: 137.3 ml/min; digoxin with clarithromycin: 133.6ml/min). In conclusion, neither erythromycin nor clarithromycin has a significant effect on serum digoxin disposition after an intravenous administration. Renal digoxin excretion is not inhibited but rather enhanced by both macrolides.

Effect of physical activity on the day‐to‐day variation in serum digoxin concentration

Physical exercise has been found to increase digoxin binding in working skeletal muscle along with a concomitant decrease in serum digoxin concentration. In a recent study on healthy volunteers, moderate physical activity during maintenance digoxin treatment was shown to decrease the renal excretion of digoxin secondary to this redistribution of the drug, thereby affecting the body content of digoxin. In the present study the influence of changes in everyday physical activities, carried out during a 10-h period after ingestion of the daily maintenance digoxin dose, on the steady-state serum digoxin concentration (24 h after the last dose) was studied in 10 digoxin-treated outpatients (61-81 years of age). Compared to normal daily activity, complete bed rest for 10 h after ingestion of the maintenance dose did not affect the steady-state serum digoxin concentration. The lack of such an influence may be explained either by a low degree of everyday physical activity in the investigated patients or to a compensatory increase in the renal excretion of digoxin during the night preceding the serum digoxin measurement. Thus, standardization of physical activity 1-2 h before blood sampling is adequate when analysing the serum digoxin concentration in elderly outpatients.

Cyclosporin and quinidine inhibition of renal digoxin excretion: evidence for luminal secretion of digoxin.

We studied the in vivo luminal and contraluminal uptake of [3H]digoxin in dog kidney using the single-pass multiple indicator dilution method. A bolus tracer of 125I-albumin (plasma reference), creatinine, or L-[14C]glucose [extracellular reference (ecf)] and [3H]digoxin (or [3H]ouabain) was injected into the left renal artery, and timed serial samples were collected from the left renal vein (basolateral uptake) and left and right ureters (luminal uptake). [3H]ouabain was excreted solely by filtration and exhibited saturable and irreversible binding at the basolateral surface. Uptake of [3H]digoxin across the basolateral membrane was large and nonsaturable. Despite urine flow-dependent reabsorption and approximately 20% protein binding, the urine recovery ratio for [3H]-digoxin/glomerular (ecf) marker was 0.97 +/- 0.04 (n = 29), indicating net digoxin secretion. After intravenous infusions of cyclosporin in Cremophor EL (0.5-3.5 microM), the urine recovery ratio decreased in a dose-dependent manner from control values of 1.13 +/- 0.06 (n = 12) to 0.62 +/- 0.03 (n = 14). There was no change in the relative renal vein recovery. Left renal artery infusion of quinidine (37.5 micrograms.min-1.kg-1) decreased the relative urine recovery of [3H]digoxin by 46% (n = 6) but had no effect on postglomerular extraction. Cyclosporin and quinidine are known inhibitors of P-glycoprotein. But digoxin did not compete with [3H]azidopine for binding in rat brush-border membranes or membranes prepared from the multidrug-resistant cell line CHRC5. The exact mechanism for renal digoxin secretion remains to be determined, but our results point to a luminal localization of this secretory system.

Effect of Physical Exercise on the Pharmacokinetics of Digoxin During Maintenance Treatment

Blood samples were taken repeatedly and urine was collected for digoxin assays on two occasions from 12 healthy male volunteers after an oral maintenance dose of digoxin. On one occasion the subjects exercised intermittently on a bicycle ergometer for 8 h after the dose. On the other occasion they rested in the supine position during the study period. Thirty and 45 min after the intake of digoxin, the serum digoxin concentration was significantly higher during exercise compared with rest, indicating increased absorption rate during exercise. Two and 4 h after the intake of digoxin, the serum digoxin concentration was significantly lower during exercise than during rest. Furthermore, the intermittent bicycle exercise decreased the renal excretion of digoxin during the study period. It also increased the steady state digoxin concentration measured after a terminating standardized period of rest. The most probable reason for these changes in the pharmacokinetics is a previously described increased binding of digoxin to exercising muscles. According to the results, there is reason to believe that the daily physical activity performed by digoxin-treated patients will determine to some extent the body content of digoxin. Changes in activity from day to day may therefore cause variations in the effect of the drug.

The digoxin-amiodarone interaction

To assess the cause of the digoxin-amiodarone interaction, the systemic availability and renal excretion of digoxin were examined in 10 patients. Patients were studied before and after 1 week and 6 weeks of concurrent amiodarone therapy, and four were also studied after 4-8 months. Mean (+/- SD) peak plasma digoxin concentration rose from 1.55 +/- 0.6 microgram /1 prior to amiodarone therapy to 2.85 +/- 1.3 micrograms/1 after 1 week of combined therapy (p less than 0.01). Mean AUC also rose from 7.2 +/- 2.1 micrograms/1.h to 12.1 +/- 6.4 micrograms/1.h (p less than 0.01) during this period. Mean peak plasma digoxin concentration and AUC remained elevated after 6 weeks and, in the patients studied, at 4-8 months. Mean urinary digoxin clearance remained unchanged. Plasma amiodarone and desethylamiodarone concentrations were consistent with the prescribed doses. This study confirmed previous findings of raised plasma digoxin concentrations following the addition of amiodarone. It has also shown that this interaction is sustained for at least several months. The cause has not been fully elucidated but does not appear to be due to a change in the renal clearance of digoxin.

Effects of verapamil on pharmacokinetics and pharmacodynamics of digitoxin in patients

Investigations by various teams have shown that combined treatment with verapamil and digoxin may result in a marked increase in digoxin plasma concentrations, necessitating a reduction in the dose of digoxin. This is mainly due to an impairment of the renal digoxin excretion. Unlike digoxin, the excretion of digitoxin is independent of renal function. A prospective clinical study was therefore planned to investigate the influence of a daily dose of 240 mg of verapamil on pharmacokinetics and the cardiac affect of digitoxin after a single dose (n = 3) and under steady-state conditions (n = 10). While pretreatment with verapamil did not alter pharmacokinectis of digitoxin in the single-doss study, there was a slight rise of digitoxin plasma concentrations (an average of 35% in 8 out of 10 patients) following administration of verapamil for a period of 4 to 6 weeks. Renal excretion of digitoxin, however, was not changed significantly. Simultaneously with a rise of digitoxin plasma concentrations and until a new steady state was reached, PQ interval was prolonged and T wave flattening intensified. On the other hand, the antagonistic effect on contractility which was intially observed after verapamil administration was diminished. Based on these observations, it can be concluded that the risk of digitals overdose after combined treatment with verapamil and digitoxin may be less pronounced than after digoxin, and that this glycoside can prove a valuable alternative.

Pharmacokinetic interactions between digoxin and other drugs

Drug interactions with digoxin are important because of this agent's narrow therapeutic index. Among the drugs that can decrease digoxin bioavailability are cholestyramine, antacid gels, kaolin-pectate, certain antimicrobial drugs and cancer chemotherapeutic agents. In selected patients, antibiotics may enhance digoxin bioavailability by eliminating intestinal flora that metabolize digoxin. Antiarrhythmic drugs, such as quinidine and amiodarone, can markedly increase steady state serum digoxin levels. Certain calcium channel blocking drugs, particularly verapamil, have a similar effect. Potassium-sparing diuretic drugs, such as spironolactone, can alter digoxin pharmacokinetics. Indomethacin may decrease renal excretion of digoxin in preterm infants. Finally, rifampin, an antibiotic used in the treatment of tuberculosis, may lower steady state serum digoxin levels in patients with severe renal disease. Physicians must maintain constant vigilance whenever medications are added to or withdrawn from a therapeutic regimen that includes digoxin.

Effects of nifedipine and diltiazem on plasma levels and renal excretion of beta-acetyldigoxin.

To determine whether nifedipine or diltiazem affect digoxin kinetics, glycoside plasma concentrations and renal excretion were measured before and during dosing in 23 patients with cardiac insufficiency achieving steady-state conditions. Mean (+/- SD) digoxin plasma concentration was 0.64 +/- 0.22 before and 0.61 +/- 0.21 ng/ml during nifedipine dosing in 11 subjects over a period of 10 to 14 days. Renal digoxin clearance was not influenced by nifedipine, whereas total body clearance and extrarenal clearance of digoxin increased slightly. In contrast, diltiazem resulted in a 24% to 70% (means = 46%) increase in plasma digoxin concentrations in eight of 12 subjects. Renal digoxin clearance was not influenced by diltiazem, whereas total body clearance and extrarenal clearance of digoxin were reduced 28% and 44% in five of the eight subjects in whom renal digoxin excretion was measured. From these data it was concluded that nifedipine has no significant effects on digoxin kinetics, but that digoxin plasma concentrations should be controlled in subjects receiving digoxin with diltiazem until new steady-state digoxin concentrations are established, and that the digoxin dose be reduced if there is evidence of toxicity.

Renal digoxin clearance: dependence on plasma digoxin and diuresis.

The renal handling of digoxin in animals involves glomerular filtration, tubular secretion and tubular reabsorption, while only glomerular filtration and tubular secretion have been described in humans. The influence of plasma digoxin and urine flow on the renal handling of digoxin was investigated in 6 healthy volunteers. Non-glomerular renal excretion of digoxin (tubular secretion minus tubular reabsorption) was inversely correlated with plasma digoxin concentration and directly with urine flow. Hence, the present study demonstrated the occurrence of tubular reabsorption in addition to glomerular filtration and tubular secretion of digoxin. The results suggest that renal clearance of digoxin should be increased by increased urine flow, which might be of importance during digoxin toxicity.

Drug Interactions with Digoxin

Multiple drug administration may affect the actions of digoxin either by altering its myocardial effects (dose-response relationship or pharmacodynamic effect) or by altering the absorption, storage or excretion of the drug (a pharmacokinetic effect). The major pharmacodynamic interactions include potentiation of digitalis toxicity by potassium-wasting diuretics and by succinlycholine. β-Blocking drugs also increase the potential for digoxin to produce adverse sinus or A-V node dysfunction. The pharmacokinetic interactions can be divided into drug interactions which alter digoxin absorption and those which change renal excretion. Estimates of the former are usually based on either steady-state or single dose studies of bioavailability. These studies have demonstrated significant reduction of absorption of oral digoxin by simultaneously administered liquid antacids, cholestyramine, kaolin-pectin, and meals of high fibre content. Reduced digoxin absorption also occurs secondary to therapy with sulphasalazine, para-aminosalicylic acid, and neomycin, probably due to their effect upon gut wall function. Propantheline and diphenoxylate with atropine, which decrease gut motility, increase digoxin absorption, whereas metoclopramide, which increases motility, depresses absorption. The renal excretion of digoxin is not changed importantly by diuretics such as frusemide but is decreased by spironolactone, possibly due to inhibition of renal tubular secretion of digoxin. Quinidine produces dramatic persistent increases in digoxin serum levels, due to decreased renal clearance of the glycoside, without changing the glomerular filtration. In addition to this renal effect, quinidine also seems to decrease the volume of distribution of digoxin, which results in acutely altered digoxin levels even within the first day after quinidine administration. Alteration of the timing of the administration of digoxin from that of a second drug (e.g. as with liquid antacids, kaolin-pectin, or meals of high fibre content), or alteration of the dose of digoxin based on the anticipated change in kinetics (as with spironolactone, quinidine or medications altering gut function or motility), can improve clinical effectiveness of digoxin therapy. However, because of individual variation in the impact of these interactions, routine monitoring of digoxin serum levels is strongly recommended under such circumstances to enhance clinical efficacy and patient safety.

The effect of quinidine on digoxin kinetics in cardiac patients.

The pharmacokinetics of digoxin was studied in 11 subjects before and during quinidine treatment. Renal clearances of digoxin and creatinine were calculated from plasma concentrations and urinary excretions of digoxin and creatinine in subjects on long-term digoxin treatment. The investigations were repeated in the same subjects during administration of quinidine. Renal clearance of digoxin decreased, while plasma concentration of digoxin and renal excretion of digoxin increased in the presence of quididine, indicating substantial changes of digoxin kinetics, induced by quinidine. The reduction in renal clearance of digoxin may be due to a specific inhibition of tubular secretion of digoxin. The considerable rise of the plasma digoxin level and the increased excretion of digoxin support the assumption of a major extrarenal mechanism of interaction.

Effect of Furosemide on Serum Clearance and Renal Excretion of Digoxin

Serum turnover and urinary excretion of digoxin with or without oral furosemide were studied in six healthy subjects who received 0.006 mg/kg body weight digoxin intravenously. During furosemide treatment, the total amount of urinary digoxin did not change but the digoxin clearance during the diuretic phase and the digoxin excretion after the diuresis decreased significantly. The average serum half-life was prolonged from 37 hours in the control period to 86 hours in the furosemide period. Decreased glomerular filtration rate by volume depletion might have been responsible for the decreased excretion of digoxin, but there was no significant difference in urine volume after diuresis between the two periods, suggesting the possibility of inhibition of tubular secretion of digoxin by furosemide. It is also possible that serum digoxin concentration may be elevated if furosemide were given more frequently.

Clinical Pharmacokinetics of Digoxin

About 70 to 80% of an oral dose of digoxin is absorbed, mainly in the proximal part of the small intestine. The degree of binding to serum albumin is 20 to 30%. Digoxin is extensively distributed in the tissues, as reflected by the large volume of distribution. High concentrations are found in the heart and kidneys, but the skeletal muscles form the largest digoxin storage. The half-life of elimination in healthy persons varies between 26 and 45 hours. The main route of elimination is renal excretion of digoxin, which is closely correlated with the glomerular filtration rate. In addition, some tubular secretion and perhaps tubular reabsorption occurs. Nearly all of the digoxin in the urine is excreted unchanged, with a small part as active metabolites. The clinical significance of dihydrodigoxin as a metabolite remains to be resolved. About 25 to 28% of digoxin is eliminated by nonrenal routes. Biliary excretion may rise up to 30% of a given dose, but the enterohepatic cycle seems to be of minor importance. The pharmacodynamic effects of digoxin, including toxic symptoms, are correlated with the uptake of digoxin in the heart after a single dose and with the steady state serum digoxin concentration during maintenance therapy. Impaired kidney function is the most important condition with an influence on the pharmacokinetics of digoxin. In addition to the renal clearance of creatinine, the biovailability of the digoxin formulation used, the volume of distribution, the amount of extrarenal clearance, body weight and serum albumin concentration, are other factors which may modify the serum level of digoxin. Certain drug interactions may also occur during the absorptive phase. Exact prediction of serum digoxin concentrations by various dosage calculations has not succeeded. Since many factors may influence the sensitivity of the myocardium to digoxin, measurement of serum digoxin levels in only one, but a useful criterion, when making clinical decisions about adjustment of digoxin dosage.

Effect of furosemide on the renal excretion of digoxin

Digoxin serum and urine levels were determined by radioimmunoassay in 6 subjects (4 patients with heart disease and 2 volunteers without heart disease) who had been maintained on oral digoxin (0.25 or 0.5 mg daily). Observations were made during a 3-day control period and then during 8 days of concomitant digoxin and oral furosemide (40 mg daily) therapy. Serum digoxin levels determined 10 and 24 hr after each dose of digoxin averaged 1.2+/-0.1 ng/ml (M+/-SE) during control and 1.3+/-0.1 during the last 3 days on digoxin and furosemide. The daily urinary excretion of digoxine averaged 51+/-6% of the oral dose during control and 52+/-6 during the entire period of furosemide administration. The renal clearance of digoxin and creatinine averaged 94+/-7 and 87+/-11 ml/min, respectively, during control; corresponding values were 88+/-8 and 85+/-9 for urine collections demonstrating a distinct diuretic effect of furosemide and 87+/-8 and 75+/-10 for urine collections not demonstrating such an effect during diuretic therapy. The results suggest that the diuretic effect of furosemide does not significantly affect the excretion of digoxin

Effect of intravenous furosemide on the renal excretion of digoxin.

The effect of an 80-mg intravenous dose of furosemide on the urinary excretion of digoxin was determined in three adult men with normal renal function, each of whom was taking 0.25 mg digoxin daily on a chronic basis. On two separate days, serum samples were taken and urine was collected every 2 hours over an 8-hour period for determination of digoxin, creatinine, calcium, and sodium concentrations. On the first day of study, a saline bolus was given intravenously, and on the second day, furosemide was given. In all subjects, urinary digoxin excretion increased after furosemide in direct proportion to the increase in urine volume. No consistent correlation was seen between digoxin excretion and creatinine, calcium, or sodium output. No significant changes in serum digoxin were found in this active study. These results are consistent with the hypothesis that increasing glomerular filtration rate or total urine volume increases the renal excretion of digoxin and may result in increased total urinary output of this glycoside.

Renal Excretion of Digoxin in Swine and Goats

In experiments on swine and goats the renal excretion of digoxin was examined, and it was found that the renal clearance of non-protein-bound digoxin in swine was lower than creatinine clearance which expresses filtration clearance. Correlation analysis showed that the renal clearance of digoxin in swine was not significantly influenced by the concentration of non-protein-bound digoxin in plasma and the pH of the urine, while there was a significant positive correlation between the clearance and the urine flow rate (Table 4). On the other hand, the renal clearance of digoxin in goats was significantly influenced by the concentration of non-proteinbound digoxin in plasma and by urine pH (Table 4). From these results it is concluded that glomerular filtration and back-diffusion are involved in the renal handling of digoxin in both swine and goats. In addition active tubular secretion is also involved in the renal excretion of digoxin in goats.

Serum levels and renal excretion of digoxin during maintenance therapy in children.

ABSTRACT. Iisalo, E. and Dahl, M. (Departments of Pharmacology and Paediatrics, University of Turku, Turku, Finland). Serum Levels and Renal Excretion of Digoxin during Maintenance Therapy in Children. Acta Paediatr Scand,63:699, 1974.—To exclude an increased excretion of digoxin as a possible reason for higher dose requirement in children a radioimmunoassay of digoxin in the serum and the 24 hr urine was carried out in 26 children, mainly infants, with congenital heart disease. This procedure was repeated on two consecutive days, in total 64 times during digoxin maintenance therapy.The daily digoxin dose per kilogram of body weight in these small children was twice as high as that used in adults. The steady state level of serum digoxin corresponded approximately to that of adults. A few fairly high digoxin levels were, however, measured in infants without any signs of digitalis toxicity.The daily excretion of digoxin in the urine during maintenance therapy was approximately the same in all age groups and on an average 47 per cent of the daily dose. This percentage is somewhat lower than that found in adults. The low renal excretion of digoxin in one newborn caused high serum digoxin levels.The higher dosage requirement of digoxin per kilogram of body weight in children as compared to adults cannot be explained with differences in the renal excretion of digoxin.

Tritiated digoxin: XIX. Turnover studies in diabetes insipidus

The effect of chronically increased urinary volumes on renal digoxin excretion and digoxin turnover was studied in 2 patients with nephritogenic diabetes insipidus and urinary volumes in excess of 9 liters/ 24 hours. The serum half-lives were 48 and 54 hours and the 7 day urinary excretion totals 46 and 41 percent, respectively. Comparison with values obtained in patients with congestive heart failure demonstrated no increase in excretion of renal digoxin. Increased urinary volume without change in glomerular filtration rate does not increase excretion of digoxin, and would not be expected to decrease the duration of digitalis toxicity.

Tritiated digoxin: XVII. Excretion and turnover times in normal donors before and after nephrectomy and in the paired recipient of the kidney after transplantation

Twenty-one tritiated digoxin turnover studies were performed in 14 subjects: 2 studies each in 7 donors, before and after unilateral nephrectomy; 1 study each in 7 recipients of the kidney after transplantation. All donors and recipients were closely related. Digoxin excretion and metabolic turnover were not significantly impaired after nephrectomy in normal donors, and combined ability of paired kidneys in different subjects was superior to the original functional excretory capacity of donors. Rejection was not a problem at the time of these studies. All recipients were receiving immunosuppressive therapy.Further evidence is provided that the renal functional capacity as determined by creatinine clearance or blood urea nitrogen is of assistance in estimating digoxin dosage in the usual patient with congestive heart failure as well as the patient with impaired renal digoxin excretion.