Total Body Clearance Of Digoxin Research Articles

Amiodarone does not affect digoxin kinetics in the rabbit.

It has been reported that amiodarone may interact with digoxin in man. We investigated the effects of amiodarone pretreatment (35 mg kg-1 day-1) on the pharmacokinetics of a single dose of digoxin (50 micrograms kg-1) in 6 rabbits. Total body clearance of digoxin was 138.84 +/- 44.67 and 147.99 +/- 29.17 ml min-1, serum half life 187.9 +/- 60.9 and 181.34 +/- 25.57 min and volume of distribution 35.4 +/- 8.54 and 37.8 +/- 3.9 litres before and after amiodarone treatment, respectively. None of these changes were statistically significant. We conclude that the presence of an amiodarone-induced change in digoxin pharmacokinetics in the rabbit was not evident and that other animal models will be necessary for studying this interaction.

Activated charcoal increases digoxin elimination in patients

Digoxin continues to be an important cause of drug toxicity. On the basis of a healthy volunteer study, activated charcoal has been proposed as a treatment for digoxin chronic intoxication. In order to evaluate the effect of activated charcoal on digoxin elimination in intoxicated patients during routine practice, we reviewed all Serum Digoxin Level Requests for adult in-patients from 1991 to 1993, with digoxin levels >2.5 ng/ml. Of a total of 39 cases, 23 had been treated with activated charcoal while 16 had not. Digoxin elimination half-life during activated charcoal therapy was 36 h (S.D. 14 h; 95% C.I. 30–42 h) while in the non-treated group it was 68 h (S.D. 19 h, 95% C.I. 57–78). Calculated total body clearance of digoxin was 55 ml/min (S.D. 17 ml/min; 95% C.I. 45–64 ml/min) for the non-treated group versus 98 ml/min (S.D. 34 ml/min; 95% C.I. 83–113 ml/min) for the group receiving charcoal, representing an 78% increase in digoxin elimination.

Effects of coadministration of propafenone on the pharmacokinetics of digoxin in healthy volunteer subjects.

Previous reports have suggested an interaction between propafenone and digoxin. We investigated the pharmacokinetics of IV digoxin when given alone (Phase I), after pretreatment with propafenone 150 mg every 8 hours for seven days (Phase II), and after propafenone 300 mg every 8 hours for 7 days (Phase III). The total body clearance of digoxin during Phase I was 2.45 ml/min/kg and was 2.17 ml/min/kg during Phase II (NS) and decreased to 1.92 ml/min/kg during Phase III (P less than 0.05). The renal clearance and half-life of digoxin were not significantly altered by propafenone. There was a trend towards a decrease in the volume of distribution of digoxin from 9.43 L/kg in Phase I, to 9.33 L/kg in Phase II, and 8.02 L/kg in Phase III. Similarly there was a trend towards a decreased nonrenal clearance of digoxin from 1.21 ml/min/kg during Phase I to 1.01 ml/min/kg during Phase II and to 0.75 ml/min/kg during Phase III. The changes in volume of distribution and nonrenal clearance parallel each other resulting in no change in the elimination half-life of digoxin. It is postulated that the mechanism of this interaction is due to decreases in the volume of distribution and nonrenal elimination of digoxin by propafenone. The degree of this interaction was related to the dose of propafenone. The magnitude of this interaction may be greater in patients and, thus, may require a reduction in the digoxin dose.

Verapamil-induced changes in digoxin kinetics and intraerythrocytic sodium concentration.

Verapamil increases plasma digoxin concentration by about 60% to 80%. To explore the clinical consequences of this interaction, we evaluated single-dose digoxin kinetics along with repeated measurements of intraerythrocytic sodium concentration in eight healthy subjects before and during verapamil coadministration. Verapamil reduced mean total body clearance of digoxin from 4.68 +/- 0.41 to 3.29 +/- 0.26 ml/min/kg and prolonged digoxin biologic t1/2 from 33.5 +/- 2.4 to 41.4 +/- 2.3 hr. These kinetic changes were associated with a greater elevation of intraerythrocytic sodium concentration than controls. Verapamil had no effect on intraerythrocytic sodium content. In vitro experiments revealed no influence of verapamil on the number of glycoside receptors on human lymphocytes. Since intracellular sodium concentration has proved to correlate closely with clinical signs of digoxin toxicity, our indicate that verapamil is likely to increase the risk of digoxin-induced arrhythmias.

Digoxin-quinidine interaction in patients with chronic renal failure.

We evaluated the effect of quinidine on digoxin pharmacokinetic in six patients with severe renal failure. Quinidine reduced the total body clearance of digoxin from 1.87 to 1.06 l/hour (p less than 0.001), and prolonged the digoxin half-life of elimination from 5.20 to 9.61 days (p less than 0.01). The digoxin volume of distribution was unchanged. Renal clearance of digoxin was negligible; thus, the decrease in total body clearance was due to a decrease in the nonrenal clearance of digoxin. The mean trough serum concentrations of quinidine ranged from 1.0 to 3.0 micrograms/ml. We conclude that in patients with chronic renal failure, the dose of digoxin should be decreased by 50% if quinidine therapy is initiated.

Pharmacokinetics of digoxin in patients subjected to the quinidine-digoxin interaction.

1 This study was designed to evaluate pharmacokinetically the digoxin-quinidine interaction in patients with atrial fibrillation. 2 Five patients on maintenance digoxin therapy were given [3H]-digoxin as a single i.v. dose before and during quinidine therapy and the elimination of [3H]-digoxin from plasma and excretion in urine were determined. 3 The mean steady state plasma concentration of digoxin increased from 0.7 to 1.3 nmol/l after quinidine administration. 4 The apparent volume of distribution of digoxin decreased on the average 38%. Renal clearance and the total body clearance of digoxin decreased 51 and 56% respectively (mean values). Also non renal clearance was reduced. The fraction of digoxin excreted unmetabolised in urine did not change during quinidine treatment. The mean elimination half life of digoxin increased from 49 to 72 h during quinidine. 5 In two patients the DC-shock did not cause a conversion to sinus rhythm. However, the quinidine induced changes in the pharmacokinetics of digoxin in these patients did not differ from the others. 6 Quinidine appears to decrease the amount of digoxin distributed to body tissue(s). In addition, the reduction of renal clearance of digoxin and the observed unchanged clearance of creatinine suggests an inhibition of the renal secretion of digoxin.

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.