Elimination Of Digitoxin Research Articles

Evidence for a digitoxin conjugating UDP-glucuronosyltransferase in the dog

Liver musomes of male Beagle dogs contain a form of UDP-glucuronyltransferase which is capable of conjugating digitoxin and its cleavage products digitoxigenin-bisdigitoxoside and digitoxigenin-monodigitoxoside. The highest reaction rates ( V max 236 pmoles/mg musomal protein min) were found for digitoxin and digitoxigenin-monodigitoxoside whereas the lowest K m was obtained for digitoxigenin-bisdigitoxoside (29 μM). Digoxin cannot be glucuronidated and digitoxigenin is glucuronidated only in traces. The result may explain the fast digitoxin elimination in dogs. Mutual induction experiments utilizing cardenolides and model substrates of UDP-glucuronyltransferase result in the conclusion that a specific form of UDP-glucuronyltransferase is responsible for glucuronidating digitoxigenin glycosides.

Bioavailability and elimination of digitoxin in patients with hepatorenal insufficiency

Following administration of digitoxin, 1 mg intravenously, the pharmacokinetics of this glycoside were studied in eight healthy volunteers and in eight patients with hepatorenal insufficiency (mean creatinine clearance 19.6 ± 2.9 ml/min; antipyrine clearance 25.6 ± 3.2 ml/min; X ± SEM). Liver cirrhosis of the patients was confirmed by liver biopsy. Plasma protein binding of digitoxin ( X ± SEM) was 95.1 ± 0.7% in the patients and 95.6 ± 1.2% in the volunteers (NS). Total body clearance of digitoxin was 0.0530 ± 0.0040 ml/min/kg of body weight in the patients and 0.0547 ± 0.0043 ml/min/kg of body weight in the healthy subjects (NS). When elimination half-lives of the patients and the volunteers were compared, there was also no significant difference (7.0 ± 0.77 days in the patient group and 7.8 ± 0.8 days in the volunteers). Our data concerning digitoxin kinetics in patients with hepatorenal insufficiency do not indicate an accumulation of the drug in these patients.

Use of Cholestyramine Resin in Digitoxin Toxicity

DIGITOXIN has a long half-life and is associated with a substantial incidence of toxicity. 1,2 It is partially excreted in the bile and later reabsorbed, contributing to its long half-life. 1,2 A nonabsorbable agent that binds digitoxin in the gut should help speed its disappearance from the serum. Cholestyramine resin, an ion exchange resin used for some hyperlipoproteinemias, appears to be such an agent. Several reports have described such a digitoxin-binding effect in animals. 3,4 This property, however, has received scant study in the digitoxin-intoxicated patient. 4-7 Recently, we encountered a patient with clinical, laboratory, and ECG evidence of digitoxin toxicity. Digitoxin elimination was studied before, during, and after administration of cholestyramine resin. The resin resulted in an accelerated elimination of digitoxin and would appear to be a valuable adjunct in therapy of patients with digitoxin toxicity. Report of a Case A 72-year-old woman was admitted to the emergency room

Digitoxin elimination reduced during quinidine therapy.

Elevated serum digoxin concentrations and clinical toxicity have been reported in patients receiving quinidine. The present study was undertaken to ascertain whether a similar interaction occurs between quinidine and another cardiac glycoside, digitoxin, and if so to evaluate the pharmacokinetic basis in five healthy volunteers. In the presence of quinidine the serum digitoxin concentration was elevated, the mean digitoxin elimination half-life was increased from 87.8 +/- 11.6 to 218.3 +/- 20.6 h (mean +/- SEM) (p < 0.01), and mean total body clearance was reduced from 5.01 +/- 1.18 to 1.87 +/- 0.20 mL/h x kg (p < 0.052). No change was observed in the apparent volume of distribution or in the volume of the central compartment for digitoxin. The data suggest that the mechanism for this interaction is a reduction in elimination and not displacement of digitoxin from tissue binding sites.

Cholestyramine and spironolactone and their combination in digitoxin elimination.

The effects of oral cholestyramine 4 gm 8 times daily and spironolactone 300 mg daily, given independently and in combination, on the elimination rate of digitoxin were studied in 6 healthy subjects pretreated with 0.1 or 0.15 mg oral digitoxin daily for 30 days before each intervention. The mean pretreatment digitoxin concentrations for the group ranged from 21 +/- 2.9 (SD) ng/ml to 28.5 +/- 6.9 ng/ml. The mean control digitoxin half-life (t 1/2) was reduced from 141.6 to 84.4 by treatment with cholestyramine alone. Treatment with spironolactone alone prolonged the mean digitoxin t 1/2 to 192.2 hr. The mean digitoxin t 1/2 after both active drugs was intermediate at 102.9 hr. Spironolactone did not fulfill the expectation from animal studies that it would enhance the clearance of digitoxin by cholestyramine. The prolongation of digitoxin elimination after spironolactone may contraindicate this drug in digitoxin intoxication.

Digoxin and digitoxin elimination in man by charcoal hemoperfusion.

Since there is no widely used causal means of reducing the severity of massive digitalis intoxication the capability of hemoperfusion with coated activated charcoal to remove toxicologically relevant amounts of digoxin and digitoxin was evaluated in vitro and in man. At a blood flow rate of 100 ml/min the digoxin clearance by hemoperfusion in vitro was 51 +/- 8 ml/min in comparison to 24.3 +/- 11.3 ml/min by hemodialysis. The average hemoperfusion clearance of digitoxin was 31.7 +/- 13.4 ml/min, whereas almost no digitoxin was removed by hemodialysis. These clearance values point to the ability of hemoperfusion of eliminating digitalis glycosides from the blood. They do not clarify the essential question whether it is possible to lower the toxic concentrations in the tissues.

Disposition of digitoxin in renal failure.

The disposition of digitoxin was studied for a period of 8 days in 6 uremic patients given a single oral dose of 1 mg 3H-digitoxin. In plasma, the time-course of radioactivity indicated a diminished absorption velocity of tritium compared to that of control subjects already reported and, after reaching of a pseudostate-equilibrium at 24 hr, an exponential decline with a mean half-life of 8.0 days. In urine, smaller amounts of tritiated compounds were eliminated in uremic patients (8.7% of the dose) than in controls (22.5%). The average fecal excretion of digitoxin and its metabolites was not significantly increased. Chloroform extraction and thin-layer chromatography in plasma, urine and feces suggested no qualitative alteration in the metabolism of digitoxin. Calculations of the total body tritium content (body stores) after each 24-hr interval and its pharmacokinetic behavior showed that the elimination of digitoxin is determined by the transfer constant from tissue to plasma. The differences in elimination kinetics of digitoxin and its metabolites of uremic patients and healthy subjects were not significant.

Studies on digitalis. III. Biliary excretion and enterohepatic circulation of digitoxin and its cardioactive metabolites.

Simultaneous serum, urine, and bile measurements of digitoxin and its cardioactive metabolites were preformed in 5 cholecystectomized patients with T tube drainage. A 86Rb method was used for serum and urine analysis. The recovery of digitoxin and cardioactive metabolites in two extractions with dichloromethane was 93%; 7% was left in bile. Peak bile concentrations had a mean value of 41.6 ng/ml and were seen after 15 to 60 min. Bile concentration was higher than serum and urine concentration after 24 hr. Mean T/2 of serum elimination was 4.3 days and 8.1 days in 5 control subjects (p less than 0.01). Mean urine concentration T/2 was 10.4 days and 7.2 days in the control subjects (not significant). Mean bile concentration T/2 was 3.5 days. Urinary excretion of digitoxin and cardioactive metabolites was the same in the two groups. The biliary fistula group excreted 22.5% in urine and bile of a dose after 8 days, whereas it was 15.8% in the control subjects. The ratio between the cumulative excretion in urine and bile varied between 1.6 and 2.2. These findings demonstrate that direct interruption of the enterohepatic circulation leads to a marked reduction in serum half-time of digitoxin and cardioactive metabolites, but T/2 is still longer than for other glycosides, indicating that factors other than the enterohepatic circulation are of importance in the slow elimination of digitoxin.

Digitoxin kinetics in patients with impaired renal function.

Serum digitoxin levels were recorded during maintenance therapy, absorption‐distribution, and elimination of digitoxin in patients with poor renal function. The analysis was carried out with a modified Rb86 method and the results were compared with results in subjects with normal renal function. During both absorption and maintenance therapy serum digitoxin levels of the patients with poor renal function were significantly lower than those of the control group. However, most of these differences could be ascribed to different concentrations of serum proteins in the two populations. When this factor was corrected for, most of the differences disappeared and became non‐significant. The elimination of digitoxin was not significantly different in the two groups. The absence of impaired digitoxin elimination during uremia indicates the development of compensatory mechanisms for the elimination of active glycosides. Although the elimination of digitoxin may be normal in uremia, the myocardial sensitivity to the drug may be changed. Digitoxin is probably the glycoside of choice in uremia, since other glycosides are more dependant on renal excretion for elimination.

Studies on the Renal Excretion of Radioactive Digitoxin in Human Subjects with Cardiac Failure

Randomly labeled C 14 -digitoxin was used in a quantitative study of the renal excretion of unchanged digitoxin and its metabolites in three human subjects with cardiac insufficiency. The elimination of approximately 60 to 80 per cent of an administered dose through the kidney suggests that the major route of elimination of digitoxin in cardiac patients is through the urinary route. There is a marked initial excretion of digitoxin during the first two days after administration of the radioactive drug followed by a gradual leveling off of the excretion gradient thereafter. Minute amounts of unchanged digitoxin have been detected in the urine up to the fortieth day after administration of a single dose of the glycoside, while C 14 -labeled compounds were detected up to the seventy-fourth day.