Studies on digitalis. IX. Some kinetic aspects of digitoxin metabolism.

The metabolic pattern of cardioactive and inactive conjugated metabolites (a maximum of 24 substances) was studied in one female and one male after a single dose of 0.6 mg digitoxin intravenously. Serum samples were obtained after 24 hr, and 24-hr urine was collected after 1, 2, 4, 6, and 8 days. With the methods used, enzymatic cleavage of conjugated bonds, thin-layer chromatography (TLC) separation, and a modified 86Rb method, the products of hydroxylation, hydrolysis, and conjugation could be separated. The Kendall rank correlation coefficient was used to compare the results from Subjects 1 and 2. Conjugation was the most rapid process, followed by hydrolysis and hydroxylation. Metabolism was progressive, leading to an increase in metabolites resulting from several enzymatic processes with time. Unchanged digitoxin reached minimum values on the fourth and sixth days and increased again on the eighth day. This indicated a continuous release of digitoxin from tissue stores and the enterohepatic circulation.

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.

Studies on digitalis. XII. Kinetic pattern of digitoxin metabolism in patients with biliary fistulas.

The metabolic pattern of cardioactive and inactive, conjugated metabolites (a maximum of 24 substances) was studied after a single intravenous dose of 0.6 mg digitoxin in two female patients (aged 72 and 62 yr) with biliary fistulas. Bile and urine were collected every twenty-fourth hour and the 1-, 2-, 4-, 6-, and 8-day samples were analyzed. With the methods used, enzymatic cleavage of conjugation bonds, TLC (thin-layer chromatography), and a modified 86Rb method, the products of hydroxylation, hydrolysis, and conjugation could be separated. All cardioactive metabolites were present in bile and all were conjugated. Unchanged digitoxin was the main substance excreted. Hydrolyzed and conjugated metabolites formed a greater part of the substances excreted in bile than hydroxylated metabolites. The metabolic pattern in bile did not change much with time. The metabolic pattern in urine showed no close resemblance to that in bile. Hydroxylated, hydrolyzed, and conjugated metabolites were equally predominant in urine. Interruption of the enterohepatic circulation by T tube drainage not only changed the elimination kinetics of digitoxin but also changed the pattern of digitoxin metabolites in urine.

Studies on digitalis. XI. Digitoxin metabolism in patients with impaired renal function.

The metabolic pattern of cardioactive and conjugated digitoxin metabolites was studied in 10 uremic patients on maintenance treatment with digitoxin 24 hr after the last dose (mean dose, 0.060 mg/day). Urine was collected over 24 hr. The mean serum digitoxin level was 9.4 ng/ml, and urine level was 6.8 ng/ml. The metabolic pattern of cardioactive metabolites was studied in 5 patients on hemodialysis. Their mean serum digitoxin level was 6.3 ng/ml and urine level was 7.3 ng/ml, on a digitoxin dose of 0.072 mg/day. Unchanged digitoxin was the main cardioactive substance present in both serum and urine of uremic patients. Uremic patients had significantly less unchanged digitoxin and had more hydroxylated (DG-3) and hydroxylated and hydrolyzed (DG-2, DG-1, and DG-0) metabolites than control patients. The extent of conjugation was the same in the two groups. Our data suggest that uremic patients produce more digitoxose than control patients and that digitoxin elimination is more rapid in uremic patients. The altered pattern of digitoxin metabolites is most consistent with uremia-induced changes in hydroxylation and hydrolysis. The hemodialysis group had a pattern of digitoxin and cardioactive metabolites similar to control patients, indicating that patients on hemodialysis differ from other uremic patients with respect to digitoxin metabolism.

Kinetics of digitoxin and the bis- and monodigitoxosides of digitoxigenin in normal subjects.

The kinetics of digitoxin and two of its metabolites, the bis- and monodigitoxosides of digitoxigenin, were determined in six normal subjects. Mean t 1/2s and total body clearances were 134.4, 15.4, and 0.59 hr and 2.66, 27.3, and 1071 ml/min. Mean renal clearance of the monodigitoxoside was more rapid (7.24 ml/min) than those of digitoxin (0.81 ml/min) or the bisdigitoxoside (0.94 ml/min). The volumes of distribution were of the same order, 0.45 l/kg for digitoxin, 0.57 l/kg for the bisdigitoxoside, and 0.83 l/kg for the monodigitoxoside. The short t 1/2 of monodigitoxoside would make it unsuitable for clinical use, but the bisdigitoxoside of digitoxigenin has a t 1/2 of an intermediate length and may have significant therapeutic advantages.

Studies on digitalis. VII. Influence of nephrotic syndrome on protein binding, pharmacokinetics, and renal excretion of digitoxin and cardioactive metabolites.

Serum protein binding of digitoxin was lower (p less than 0.05) in 7 patients with nephrotic syndrome (96.2%, SD 1.4) than in 51 control patients (97.3%, SD 0.5). Urine protein binding of digitoxin was 60.1% in the 6 nephrotic patients in whom it was determined. Simultaneous serum and urine measurements of digitoxin and cardioactive metabolites were performed in 5 patients after a single intravenous dose of 0.6 mg digitoxin. A modified 86Rb method was used. Mean T/2 of serum elimation was 4.8 days and 8.1 days in 5 control subjects (p less than 0.05). Serum concentrations 24 hr after the dose were lower in the nephrotic group (p less than 0.0025). The urine concentration T/2 with a mean value of 5.0 days was not significantly different from controls (7.2 days). The cumulative renal exeretion was higher in the nephrotic group (23.2% of dose) than in controls (15.8%) for 8 days. The excretion during one serum T/2 was the same in the two groups. Increased renal excretion thus explains the shortened serum T/2 in nephrotic patients. Preliminary data on the metabolic pattern of digitoxin and cardioactive metabolites in serum and urine suggested that drug metabolism may be changed in patients with nephrotic syndrome. As renal excretion is enhanced, patients with nephrotic syndrome will require higher doses of digitoxin. They should be maintained at lower than usual serum levels of total drug due apparent increased volume of distribution and hypoalbuminemia with consequent increased free drug fraction.

Effects of verapamil, diltiazem, and nifedipine on plasma levels and renal excretion of digitoxin.

To determine whether verapamil, diltiazem, or nifedipine affect digitoxin kinetics, glycoside plasma concentrations and renal excretion were measured before and during steady-state dosing in 30 patients with cardiac insufficiency. The mean (+/- SD) digitoxin plasma concentration was 14.27 +/- 3.66 ng/ml before and 18.15 +/- 5.33 ng/ml during verapamil dosing in 10 patients over a period of 4 to 6 weeks. Renal digitoxin clearance was not influenced by verapamil, but total body clearance and extrarenal clearance of digitoxin were reduced by 27% and 29%, respectively. Diltiazem resulted in a 6% to 31% (mean = 21%) increase in plasma digitoxin concentrations in five of 10 patients because of reduced extrarenal clearance of digitoxin. In contrast to verapamil, the concomitant dosing of nifedipine over 4 to 6 weeks did not alter digitoxin plasma levels or daily renal excretion. Based on these observations, the risk of digitalis intoxication after combined dosing with verapamil and digitoxin is much less pronounced than that after digoxin, and thus this glycoside is a valuable alternative.

Digitalis pharmacokinetics and metabolism.

The pharmacokinetics of the cardiac glycofides have been elucidated as a result of the development of assays of sufficient sensitivity to measure the concentration of digitalis compounds in biological fluids. Digoxin can accumulate in the body without the administration of a loading dose, and a steady state blood concentration will be reached in 5 to 7 days. Digitoxin requires 35 days to accumulate to a plateau. If a loading dose of digoxin is used, it should be approximately three times the estimated daily maintenance dose. Factors that determine the selection of the appropriate maintenance dose of digoxin include renal function and lean body mass. Digitoxin is less dependent on renal function for its elimination than is digoxin. Knowledge of the pharmacokinetics of digitalis preparations is useful in determining how to change from one cardiac glycoside to another, each with different half-lives. One should wait 3 days before starting digoxin therapy when changing from maintenance digitoxin to digoxin (assuming normal renal function). The pharmacokinetics of changing from ouabain to digoxin without loss of digitalis effect are described. The metabolism of the commonly used digitalis preparations are summarized.

Treatment of a patient with severe digitoxin intoxication by Fab fragments of anti-digitalis antibodies.

A massive digitoxin (DGTX) intoxication in a 36-year-old man (35 mg DGTX) was treated by prolonged and repeated i.v.-infusions of Fab fragments of anti-digitalis antibodies (FAB). Blood and urine samples were collected over a 98 h period for monitoring the efficacy and adequacy of FAB treatment. DGTX concentrations were determined after protein precipitation (release of FAB-bound and protein-bound DGTX) in unprocessed serum and urine samples, and after aliquots of these samples had been dialysed in vitro against DGTX-free buffer (elimination of DGTX not bound to FAB). The difference in DGTX concentration between the unprocessed and dialysed samples was the amount of DGTX bound to plasma proteins and the small fraction of unbound DGTX being relevant for the therapeutic and toxic effects of the drug. Before FAB therapy was started, the total serum DGTX concentration was 535 nmol/l. The first FAB infusion (320 mg) was started 11 h after drug ingestion. Since this amount of FAB was insufficient to bind all DGTX present in the serum, cardiac DGTX toxicity (total AV-block) persisted. During a second FAB infusion (400 mg) the patient reverted to regular AV-conduction. At this time most of the DGTX in serum was FAB-bound. Toxic symptoms (sinus arrest) reappeared twice and were accompanied by increasing amounts of non-antibody-bound DGTX in the serum. Additional application of FAB (2 x 80 mg) resulted in the immediate disappearance of arrhythmia. During FAB-treatment total DGTX serum concentrations and renal DGTX clearance rose, indicating redistribution of drug from tissue to serum and urinary elimination of FAB-bound DGTX, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Digitoxin elimination in healthy subjects taking ampicillin.

The present study was carried out to evaluate the changes in digitoxin kinetics during ampicillin administration. Subjects were informed of the nature of the study and the treatment was applied to those who gave their written consent. Six healthy volunteers received a single oral dose of 1.0 mg of digitoxin. Three days later, they were given orally ampicillin trihydrate, 500 mg four times daily, for five consecutive days. Blood samples were taken at 24, 36, 48, 60, 72, 96, 120, 144, 168 and 192 hours after digitoxin. Compliance with ampicillin regimen was verified by fluorimetric measurement of serum ampicillin. Concentrations of serum digitoxin were determined by radioimmunoassay. The mean digitoxin elimination half-life changed from 162.8 +/- 12.9 h before to 181.3 +/- 10.1 h (mean +/- s.e. mean) after ampicillin. These differences were not significant. No consistent evidence of a kinetic interaction between digitoxin and the broad-spectrum antibiotic ampicillin was found.

Digitoxin and its metabolites in patients with liver cirrhosis.

Pharmacokinetic profile and urinary excretion of digitoxin and 4 metabolites were investigated in 9 patients with biopsy confirmed liver cirrhosis (median antipyrine clearance 20.0 +/- 5.4 ml/min; X +/- SEM) and were compared with that of 8 healthy volunteers (antipyrine clearance 36.9 +/- 4.9 ml/min) following intravenous and p.o. administration of 1 mg digitoxin. The kinetic parameters derived from the digotoxin plasma concentration time curve and from urinary recovery including total clearance of unchanged digitoxin did not differ significantly between both groups investigated. Renal clearance of digitoxin was 0.017 +/- 0.005 ml/min/kg in the patient group and 0.011 +/- 0.002 ml/min/kg in the volunteers (NS); it was 0.00340 +/- 0.00047 ml/min/kg and 0.00223 +/- 0.00039 ml/min/kg, respectively for digitoxigenin-bis-digitoxoside (NS), 0.00006 +/- 0.00001 ml/min/kg and 0.00016 +/- 0.00005 ml/min/kg for digitoxigenin-mono-digitoxoside (P < 0.05), 0.00041 +/- 0.00013 ml/min/kg and 0.00088 +/- 0.00032 ml/min/kg for digitoxigenin (P < 0.05), 0.00135 +/- 0.00049 ml/min/kg and 0.00113 +/- 0.00042 ml/min/kg for digoxin (NS). In conclusion, hydrolysis of digitoxin is altered in liver cirrhosis, whereby a significant reduction in the renal clearance and urinary recovery of digitoxigenin-mono-digitoxoside and digitoxigenin was seen in the present study.