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PubMed2005

Role of organic anion transporting polypeptide 2 in pharmacokinetics of digoxin and beta-methyldigoxin in rats.

Recently, we found that potent P-glycoprotein (P-gp) inhibitors, such as verapamil and cyclosporin A, markedly modulated the pharmacokinetics of digoxin in rats, whereas they did not affect beta-methyldigoxin pharmacokinetics significantly. Digoxin is also a substrate of rat organic anion transporting polypeptide 2 (Oatp2). Here, we compared the magnitude of Oatp2-mediated drug interaction of digoxin and beta-methyldigoxin using amiodarone as an Oatp2 inhibitor in rats. Amiodarone (20 mg/kg) given intravenously significantly increased plasma levels and decreased biliary excretion, liver distribution, and intestinal distribution of digoxin administered intravenously at a dose of 10 mug/kg. Amiodarone also significantly decreased biliary excretion and liver distribution of beta-methyldigoxin, but the change in plasma levels of beta-methyldigoxin was quite small. These findings may give a clue in selecting these cardiac glycosides in clinical pharmacotherapy for patients receiving multiple drugs towards escape from Oatp2-mediated drug interactions.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1979

Interaction of digoxin and montmorillonite: mechanism of adsorption and degradation.

IR, X-ray diffraction, and absorption studies showed that digoxin is adsorbed onto montmorillonite by a reversible adsorption mechanism at pH 2 and 6. Degradation studies indicated abnormally high acid hydrolysis rates for digoxin interacted with montmorillonite. Accelerated digoxin degradation is attributed to the ability of the clay surface to concentrate both digoxin and protons. The effective pH at the clay surface appeared to be 1.5 pH unites lower than the bulk suspension pH. Bisdigoxigenin was the major adsorbed degradation product. A similar catalytic effect also may occur with other neutral drugs that degrade by acid hydrolysis and should be considered in the formulation of clay-containing drug products or their coadministration with other drugs.

Adsorption↗
PubMed1984

Kinetics of partitioning and binding of digoxin and its analogues in the subcompartments of blood.

The kinetics of digoxin and analogues (metabolites) in the subcompartments of blood, erythrocytes and plasma, were first order and concentration independent. The rate and extent of red blood cell partitioning of the tested compounds were, according to first-order kinetics, identical in the presence and absence of structurally related compounds and dependent on lipophilicity and temperature; red blood cell penetration was a reversible process. Erythrocyte partitioning of digoxin and its analogues was postulated to be by passive diffusion. There was significant intracellular binding of the compounds, and hemoglobin was the major ligand. The kinetics of red blood cell partitioning of the individual compounds were fitted according to a closed two- or three-compartment modeL. The latter indicated the existence of two kinetically separable compartments within the red blood cells. Model-independent mean transit times of red blood cell-plasma water partitioning of the compounds depended largely on the lipophilicity and were a thousand times greater for the least lipophilic analogues than for the most lipophilic derivatives. Red blood cell partitioning of digoxin and its metabolites under in vivo and in vitro conditions, were equivalent. Plasma protein binding of the tested compounds was concentration independent, unaltered in the presence of the analogues, and temperature independent between 24 degrees C and 37 degrees C. Binding to albumin in buffer solution was significantly larger than to albumin in plasma for all the compounds. Binding of digoxin and its analogues to albumin in buffer solution increased with increasing lipophilicity of the compounds.

Albumins↗
PubMed2002

Protective effects of poly (ADP-ribose) synthase inhibitors on digoxin-induced cardiotoxicity in guinea-pig isolated hearts.

Reactive oxygen species, generated and released during digoxin-induced cardiotoxicity, can produce an activation of poly (ADP-ribose) synthase (PARS). Our objective was to examine the effects of PARS inhibitors, 3-aminobenzamide (3-AB ) and nicotinamide, on digoxin-induced arrhythmias in guinea-pig isolated hearts. 3-AB (0.1-0.3 mM) and nicotinamide (0.3 mM) were added to the perfusion solution starting 10 min before digoxin infusion (8 microg x ml (-1)min (-1)reaching the heart) and maintained throughout the experiments. Electrocardiograms and coronary perfusion pressure were recorded continuously, and digoxin-induced arrhythmias were determined. Nicotinamide markedly inhibited ventricular tachycardia (VT) incidence (from 100%, n= 7, to 29%, n= 7), and abolished ventricular fibrillation (VF) incidence. 3-AB (0.1 mM, n= 9) significantly decreased VT incidence from 100% ( n= 7) to 22% ( n= 9) and VF incidence from 86% ( n= 7) to 11% ( n= 9). Both nicotinamide and 3-AB (0.1 mM) markedly decreased number of ventricular ectopic beats (VEBs) and arrhythmia score. 3-AB at 0.3 mM ( n= 8) appeared to decrease the VT (to 63%) and VF incidence (to 38%), but these reductions did not reach statistically significance levels. Moreover, 3-AB at high concentration (0.3 mM) did not significantly modify the number of VEBs and arrhythmia score. There were no significant changes in coronary perfusion pressure, heart rate or pressure rate index measured at certain time points throughout the experiment in all groups. Our results suggest that PARS activation plays a role in the digitalis-induced cardiotoxicity in guinea-pig isolated hearts.

Animals↗
PubMed1984

Serum levels of digoxin in sudden cardiac deaths.

Digoxin was determined in postmortem serum samples from 100 patients who died suddenly of cardiac disease. Twenty patients had digoxin levels below the therapeutic range. Twenty-one patients had normal values within the therapeutic range (1.2-2.5 nmol/l). In ten cases there was probably an overdosage. Another 15 patients had markedly elevated levels. No digoxin concentration was found (below 0.5 nmol/l) in 34 patients. The importance of determination of digoxin levels both by the clinician and the pathologist is stressed as well as the necessity of using a correct sampling technique at autopsy.

Aged↗
PubMed1985

[Distribution of digoxin, digitoxin and their cardioactive metabolites in human heart and kidney tissue. A postmortem study].

A method was developed for the specific determination of digoxin and digitoxin, as well as their semisynthetic derivatives and dependent cardioactive metabolites, in autopsy samples of heart and kidney. A collective of six patients on long-term treatment with therapeutic doses of beta-acetyldigoxin had a mean myocardial digoxin content of 46.1 +/- 25.0 ng/g (SD); kidney: 50.3 +/- 30.3 ng/g. Digoxigenin bisdigitoxoside represented the second most important metabolite in heart and kidney; digoxigenin monodigitoxoside and digoxigenin follow, respectively. In a collective of seven patients on maintenance treatment with digitoxin, the mean tissue levels were higher but the metabolic pattern was similar (myocardial digitoxin content: 78.9 +/- 38.4 ng/g, renal content: 104.1 +/- 44.1 ng/g). The amount of digoxin formed by hydroxylation under long-term treatment with digitoxin in heart and kidney were approximately 10 ng/g. A case of digoxin intoxication differed both in the tissue content and in the metabolic distribution.

Adult↗
PubMed1983

Digoxin-related impairment of learning and memory in cardiac patients.

The relationship between the plasma level of the cardiac glycoside digoxin and performance on a range of cognitive tasks was investigated in a group of cardiac outpatients on maintenance therapy. The cognitive functions assessed were speed of decision-making and recognition memory of nonverbal and verbal material, competitive audio-visual attention performance, visuo-motor-choice reaction time and auditory verbal learning (AVL). Multiple regression analysis of the data revealed a strong relationship between plasma digoxin level at the time of testing and the number of trials to criterion in the AVL task (plasma digoxin level 0.7-1.8 nmol/l). Further data analysis indicated that this association was unlikely to be due to age, education or severity of cardiac disorder. The results strongly suggest that an increasing plasma level of digoxin may produce a progressive deterioration in auditory verbal learning and short-term memory.

Adult↗
PubMed1979

Digoxin induced release of creatine kinase from isolated guinea-pig hearts.

In isolated perfused guinea-pig hearts, digoxin produced a concentration dependent release of creatine kinase (ATP-creatine-transphosphorylase; CK). A corresponding decrease of the CK activity in the myocardium was obtained. The enzyme release seems to be a sign of glycoside intoxication, as its extent paralleled the severity of digoxin induced arrhythmias. Especially high CK activities were liberated when ventricular fibrillation occurred. Likewise, electrically induced fibrillation, in control hearts, led to enzyme release. However, the digoxin effect was not matched. Reserpine pretreatment antagonized the CK release by electrical fibrillation, whereas it increased excessively the enzyme liberating effect of higher digoxin concentrations. Also, propranolol decreased the enzyme release due to electrical fibrillation. The glycoside induced CK liberation, however, was not diminished, although the ventricular fibrillation was prevented. Increase of the potassium concentration of the perfusion fluid prevented the glycoside induced fibrillation, and reduced the enzyme release. The significance of the enzyme loss from the myocardium, and the mechanisms of enzyme release are discussed.

Adrenergic beta-Antagonists↗
PubMed1975

Inotropic action, myocardial uptake and subcellular distribution of ouabain, digoxin and digitoxin in isolated rat hearts.

In experiments on isolated, electrically driven (240/min) rat hearts, perfused via the aorta at a constant flow (3.8 ml/min), the pharmacologically effective concentration range, the myocardial uptake and the subcellular distribution of three cardiac glycosides (digitoxin, digoxin, ouabain) were determined. The following results were obtained: 1. The effective range varied depending on the cardiac glycoside tested: With digoxin and ouabain very similar results were found- the positive inotropic concentration ranges being within 8x10(-6)M and 6x10(-5)M, the maximum positive inotropic effects attainable being about 100% and the concentration for half maximum effects (ED-50) being 2.4x10(-5)M and 2.3x10(-5)M, respectively. With digitoxin the inotropic concentration range was found to be within 3.6x10(-6)M and 2.4x10(-5)M with a maximum inotropic effect attainable of about 50% only and an ED-50 of 9.5x10(-6)M. The analysis of the time course of the inotropic action revealed extremely short half times for all cardiac glycosides studied (between 48 and 54 sec). 2. The myocardial uptake correlated with the physicochemical behaviour of the three cardiac glycosides studied and was found-depending on the perfusion time (5 to 60 min)-to be in the range of 23 and 36 (ouabain), 66 and 98 (digoxin) and 169 and 264 (digitoxin) nmoles/g wet weight. The respective computed half times for these uptake processes were 2.5 min (digoxin, ouabain) and 3.4 min )digitoxin). 3. Regarding the subcellular distribution an accumulation exceeding an "unspecific" binding (non-perfused hearts) was found mainly in the nuclear-membrane fraction. On the basis of these results (very short half times of either the pharmacological action and the cardiac uptake) the site of action of cardiac glycosides in the rat heart is supposed to be located at the surface membrane of the heart muscle cells. Furthermore, the above results are discussed with respect to those obtained in digitalis-sensitive species.

Animals↗
PubMed1976

The uptake and subcellular distribution of radio-labeled metabolites of digoxin in the isolated perfused guinea-pig heart.

Cardiac glycosides like digitoxin and digoxin with three digitoxoside sugar residues have been reported to undergo step-wise degradation to yield the corresponding genins, and the importance of the digitoxoside side-chain for the pharmaco-dynamics property of cardiac glycosides has also been suggested. A sytematic study was therefore undertaken on the cleavage products of digoxin. Digoxigenin-bis-digiitoxoside (with two sugar residues) digoxigenin-monodigitoxoside (with one sugar residue) and digoxigenin (with no sugar) were compared with the parent compound, digoxin. The radio-labeled compounds were perfused through isolated guinea pig hearts using 10-7 M concentration in the perfusion medium for a fixed period of 64 min followed by an 8 min period of wash-out with normal medium. The uptake and sub-cellular distribution of the drugs were thereafter measured scintillation counting. All the compounds produced postive inotropic responses, the mondigitoxoside producing the greatest effect, digoxigenin next in order of inotropic response magnitude, the bis-digitoxoside produced the least effect, and digoxin was intermediate between the genin and bis-digitoxoside. The uptake of the monodigitoxoside was the highest, and in general, the quantitative uptake was related to the inotropic response. The greatest binding of each digitoxoside was found in the microsomal fraction. Both mechanical activity and uptake of all four drugs were uniformly reduced by an increase in potassium concentration in the perfusion medium.

Animals↗
PubMed1988

The effect of renal and hepatic impairment and of spironolactone on digoxin immunoassays.

The effect of renal and/or hepatic dysfunction, and of concomitant spironolactone therapy, on seven commercial digoxin assays was evaluated in 45 patients taking both these drugs, and a comparison made with the digoxin concentrations measured using the same assays in 30 patients taking digoxin in the absence of spironolactone. The study showed that increasing renal dysfunction resulted in increasing inaccuracy in assay results with the methods tested. The influence of concomitant spironolactone was to produce a further distortion, which was shown to be additive in patients with impaired renal and/or liver function. The results highlight the unresolved specificity problems which persist in many, if not all, of the immunoassays currently offered to clinical laboratories which, if not recognised, could significantly influence digoxin therapy and patient management.

Aged↗
PubMed1983

Effect of coadministration of verapamil and quinidine on serum digoxin concentration.

Both quinidine and verapamil are known to increase the serum digoxin concentration (SDC), and other calcium channel blockers may have a similar effect. Since an increasing number of patients is likely to be treated concurrently with digoxin, quinidine and a calcium channel blocker, a study was done to show whether coadministered quinidine and verapamil would cooperate to elevate the SDC. Nine healthy volunteers on basic digoxin treatment (Leanoxin 0.125 mg t.i.d.) were treated with placebo, verapamil 80 mg t.i.d. and the combination (verapamil 80 mg plus quinidine base 160 mg t.i.d.), for 2 weeks in a randomized sequence. Drug concentration and various cardiovascular parameters were measured each week and/or at the end of each treatment period. Steady state concentrations were always obtained within 1 week and drug levels at the end of the first and second weeks of treatment were almost identical. The plasma verapamil concentration (PVC) was 25.8 +/- 9.9 ng/ml during coadministration of verapamil and digoxin, and 15.7 +/- 6.9 ng/ml during combined verapamil-quinidine coadministration, when the serum quinidine concentration (SQC) was 1.26 +/- 0.50 micrograms/ml. Compared to placebo SDC rose by 53% from 0.62 +/- 0.16 to 0.95 +/- 0.29 ng/ml (p less than 0.001) during verapamil treatment and further to 1.58 +/- 0.38 ng/ml (155% rise; p less than 0.001) during combined verapamil-quinidine coadministration. Thus each drug maintained its own effect on SDC in the presence of the other, and their actions became combined in increasing the SDC.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1983

Fasting and postprandial absorption of digoxin from a microencapsulated formulation.

The absorption of digoxin from a capsule preparation containing a large number of small, enteric-coated granules of the glycoside (Preparation CR) was compared in 10 volunteers with that from a rapidly dissolving tablet (Preparation L). Plasma and urine digoxin concentrations were measured by radioimmunoassay. In the fasting state, after a loading dose of digoxin (0.76 mg), peak plasma concentrations were significantly (p less than 0.001) lower after CR (2.0 +/- 0.5 nmol/l, mean +/- SD) than L (4.7 +/- 1.1 nmol/l). Peak concentrations after CR were significantly (p less than 0.001) delayed compared to L (3.3 +/- 0.6 h vs 1.1 +/- 0.4 h). Also, postprandial peak plasma concentrations at steady state, were significantly (p less than 0.01) lower after CR (1.0 +/- 0.3 nmol/l) than L (2.7 +/- 0.5 nmol/l), and the peak concentrations occurred later (3.9 +/- 1.7 h vs 1.4 +/- 0.9 h). The area under the plasma concentration-time curves was smaller (p less than 0.01) for CR (17.7 +/- 5.9 nmol X 1(-1) X h) than for L (22.4 +/- 4.1 nmol X 1(-1) X h), and so was the amount of drug excreted in urine (174 +/- 25 micrograms vs 190 +/- 31 micrograms; p less than 0.005). Thus, the absorption rate of digoxin from the enteric-coated formulation was markedly reduced but at the cost of a variable reduction in the amount absorbed.

Adult↗
PubMed1983

Pharmacokinetics of digoxin in pregnancy.

Digoxin-renal-clearance, creatinine-clearance, 24-h urine elimination of digoxin and serum digoxin were studied in 15 patients in the third trimester of pregnancy and 6 to 12 weeks post-partum. There was significant fall post-partum in the first three. There was also a significant fall post-partum in serum digoxin levels. This finding was unexpected, but may be due to heightened absorption exceeding increased elimination because of the physiological status in pregnancy.

Creatinine↗
PubMed1981

Interindividual differences in the pharmacokinetics of digitoxin and digoxin during long-term treatment.

Patients suffering from congestive heart failure received maintenance doses of digitoxin (N = 10) or digoxin (N = 8). The plasma glycoside concentration was determined, and after a single dose of 3H-digitoxin or 3H-digoxin, the decline and excretion of radioactivity were measured over a period of 7 (digitoxin) and 3 days (digoxin). Plasma radioactivity declined with a T1/2 beta between 77 and 234 h (mean 138 h) in the case of digitoxin and with a T1/2 beta between 9.2 and 38.6 h (mean 23.5 h) for digoxin. A close correlation between T1/2 beta and excreted radioactivity and T1/2 beta and total plasma level was found for digitoxin. In 4 patients TLC of urine showed that interindividual variations in digitoxin elimination could possibly be attributed to variation in metabolism, resulting in the production of different metabolites. Predicted digitoxin plasma levels agreed well with measured values. The maintenance dose could be calculated from the total body clearance (VCl) and a presumed plasma glycoside level. The recommended technique facilitates dosage calculations in patients treated with digitoxin.

Adult↗
PubMed1981

Effect of dose on bioavailability of oral digoxin.

Nine healthy volunteers received single 0.25, 0.5, 1.0, 1.5, and 2.0 mg doses of oral digoxin tablets in random sequence on five occasions separated by at least 4 weeks. Urinary excretion of immunoassayable digoxin was determined from 8 consecutive 24 h urine samples collected after each dose. Mean values of cumulative urinary excretion of digoxin at the 5 doses were: 40.9, 35.6, 36.4, 34.1, and 33.5% of the dose (F = 0.64; d.f. = 4.32; N.S.). Mean values of urinary excretion half-life were: 2.48, 2.03, 2.20, 2.07, and 1.87 days (F = 2.87; d.f. = 4.32; p = 0. 05). Thus, the bioavailability of orally administered digoxin tablets in healthy volunteers is dose-independent over an 8-fold range of doses.

Administration, Oral↗
PubMed1989

Serum digoxin and beta-methyldigoxin in elderly patients on hospital admission: correlation with home compliance and clinical variables.

Serum digoxin and beta-methyldigoxin (BMD) were measured in 165 elderly patients (age greater than 60 years) admitted to hospital, of whom 109 had been treated at home with digoxin and 56 with BMD. The mean BMD level was significantly lower than that of digoxin (1.1 vs. 1.4 ng/ml). Creatinine clearance and daily dose were the variables most strongly associated with digoxin level, and the prescribed dose and serum albumin were the best predictors of the BMD concentration. Compliance was assessed by a compliance index (CI), namely the ratio of the measured glycoside concentration, corrected for creatinine clearance, over the expected steady-state dose, calculated from a hospitalized reference group. Compliant individuals in both treatment groups, i.e. those with a CI greater than the median value, were characterized by a lower daily dose and dosage frequency. Toxicity, whether clinical or electrocardiographic, was present in 9% of the patients and was associated only with a significantly higher mean serum level of the drug.

Aged↗
PubMed1976

Absorption of beta-methyl-digoxin determined after a single dose and under steady state conditions.

Single doses of beta-methyl-digoxin 0.4 mg were given to groups of 17-18 healthy volunteers as an intravenous infusion lasting 2 hours, or orally as Lanitop Liquidum or Lanitop tablets. The serum glycoside concentration and urinary glycoside excretion were measured over 8 and 32 h. The absolute bioavailability from the oral preparations in comparison with the infusion was lower for the first 8 h than for the entire 32 h of the investigation; the relative bioavailability from tablets was the same as from the solution for both periods. For both periods the area under the serum concentration/time curve and the urinary glycoside excretion were significantly lower after administration of the tablets than after intravenous infusion. Taking the average of both parameters, the absolute bioavailability of beta-methyl-digoxin was about 80% from the solution and about 70% from the tablets. In 18 patients undergoing intravenous or oral therapy with beta-methyl-digoxin steady state glycoside concentration were compared in a cross-over study of intravenous maintenance therapy with Lanitop ampoules or oral treatment with Lanitop tablets. For a standard daily dose of 0.2 mg beta-methyl-digoxin the serum concentrations were 1.35 +/- 0.10 ng/ml during both intravenous and oral administration. The intra-individual variation in glycoside concentration after changing from intravenous to oral maintenance therapy, or vice versa, was about the same as during continued intravenous or oral administration. It is concluded that the rate of rise of serum concentration after a single dose may be a useful indicator of the rate of absorption, but that the area under the serum concentration/time curve and the urinary glycoside excretion up to 32 h are unsuitable for determining equivalent doses of different formulations or routes of administration of digitalis glycosides.

Administration, Oral↗