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PubMed1986

Facilitation of lethal ventricular arrhythmias by therapeutic digoxin in conscious post infarction dogs.

The proarrhythmic potential of digoxin, administered in a therapeutic dosage regimen, was evaluated in conscious dogs in the subacute phase of myocardial infarction. In this evaluation, digoxin (0.0125 mg/kg/day intravenously) or vehicle were administered to conscious dogs for periods of 5 to 7 days, commencing 4 to 5 days after anterior myocardial infarction. Before treatment, programmed ventricular stimulation failed to initiate ventricular tachycardia in 26 post infarction dogs. After treatment, programmed stimulation initiated ventricular tachyarrhythmias in only 1 of 13 digoxin-treated dogs (1.36 +/- 0.17 ng/ml serum digoxin) and in 0 of 13 vehicle-treated dogs. However, the incidences of early ventricular fibrilation (4 of 10 digoxin vs 0 of 12 vehicle; p less than 0.05) and of 24-hour mortality (6 of 10 digoxin vs 2 of 12 vehicle; p less than 0.05) occurring in response to the development of posterolateral ischemia in the presence of previous anterior myocardial infarction was significantly greater in digoxin-treated (1.47 +/- 0.19 ng/ml serum digoxin) than in vehicle-treated animals. These findings suggest an enhanced susceptibility toward the development of ischemia-related lethal arrhythmias in the presence of therapeutic digoxin serum concentrations early after myocardial infarction, which is not predicted by programmed ventricular stimulation testing.

Animals↗
PubMed1981

Effect of quinidine on positive inotropic action of digoxin.

To determine whether digoxin-quinidine interaction alters the inotropic effect of the glycoside, the response of peak isometric force and maximal rate of force development (dF/dt) in isolated feline right ventricular papillary muscles to digoxin and quinidine alone, and in various combinations, was examined. The administration of 1.3 or 2.6 x 10(-5) M of quinidine after 2 x 10(-7) M of digoxin resulted in an increase in contractile performance in each animal. Although 1.3 x 10(-5) M of quinidine alone produced a positive inotropic effect, 2.6 x 10(-5) M of quinidine produced no such effect. Because myocardial digoxin content has been reported to decline after administration of quinidine these results suggest that the increase in contractile performance when quinidine was administered after digoxin is due to displacement of digoxin from less to more active myocardial sites. The administration of 2 or 4 x 10(-7) M of digoxin after 2.6 x 10(-5) M of quinidine resulted in a minimal increase in force and rate of force development. A similar inhibition of the inotropic effect of digoxin was found in rabbit papillary muscles pretreated with quinidine. Inhibition was not limited to digoxin because pretreatment of muscles with quinidine also inhibited the inotropic effect of acetylstrophanthidin. Thus, quinidine has diametrically opposite effects on digitalis-induced inotropy dependent on the sequence with which the drugs are administered.

Animals↗
PubMed1981

Quinidine-digoxin interaction: time course and pharmacokinetics.

The time course of the rise in serum digoxin concentration was followed in 18 patients treated with digoxin as quinidine treatment was started with a loading dose. The mean serum digoxin levels rose significantly during the first 24 hours after administration of quinidine was begun, and reached a new steady state concentration after about 48 hours. Digoxin kinetics were studied in two groups of normal volunteers: Group 1 (n = 7) received a small dose of quinidine, 800 mg/day, and group II (n = 8) received 1,600 mg/day. There was no significant mean change in the apparent volume of distribution of digoxin in either group. In group I (small dose), quinidine reduced the digoxin clearance values: total clearance by 30 percent, renal clearance by 32 percent and nonrenal clearance by 29 percent. In group II (large dose), quinidine reduced digoxin total clearance by 36 percent, renal clearance by 54 percent and nonrenal clearance by 22 percent. The reduction in digoxin volume of distribution and renal clearance during quinidine treatment were a function of the serum quinidine concentration. The change in nonrenal clearance of digoxin was independent of serum quinidine concentration.

Adult↗
PubMed1992

Review of randomized trials of digoxin therapy in patients with chronic heart failure.

Although digitalis glycosides were introduced in the treatment of cardiac maladies greater than 200 years ago, controversy persists regarding the precise role of digoxin in any multidrug approach to the treatment of congestive heart failure (CHF). Despite its widespread use for more than 2 centuries, only recently have double-blind, randomized, placebo-controlled trials of digoxin therapy been conducted in patients with moderate CHF and sinus rhythm. These trials demonstrate that digoxin is superior to placebo in improving left ventricular (LV) ejection fraction, increasing exercise capacity, and preventing CHF worsening. Digoxin produces benefits similar to those seen with angiotensin converting enzyme (ACE) inhibitors with regard to clinical compensation and improvement in LV function. However, improved survival is demonstrated only in response to ACE inhibitors. The recently completed RADIANCE study addresses the value of combining digoxin with ACE inhibitor therapy in patients with mild-to-moderate CHF. Because increased mortality has been reported with the newer oral inotropic agents, it currently appears that digoxin is the only oral inotropic agent useful in clinical practice in the treatment of CHF. However, the effects of digoxin on mortality in patients with CHF remain unknown. In the large, double-blind, randomized trial conducted by the National Heart, Lung, and Blood Institute, the effects of digoxin on mortality in patients with CHF and already being treated with ACE inhibitors are currently being evaluated. Presently, based on the results of placebo-controlled studies, it appears that digoxin, alone or in combination with ACE inhibitors, is beneficial in patients with any signs or symptoms of CHF due to systolic LV dysfunction.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1990

The effect of age on digoxin pharmacokinetics in Fischer-344 rats.

Digoxin protein binding and pharmacokinetics were studied in 4-, 14-, and 25-month-old male Fischer-344 rats to determine if there were age-dependent changes in digoxin disposition. Serum protein binding did not differ among age groups. The average percentage unbound digoxin for all animals was 61.3 +/- 5.3% (means +/- SD, n = 15). For pharmacokinetic studies, [3H]digoxin and 1 mg/kg unlabeled digoxin were administered as an intravenous bolus dose to animals from each age group. The [3H]digoxin terminal elimination half-life was 2.0, 2.3, and 2.5 hr, respectively. The steady-state volume of distribution in the three age groups was 1.51, 1.49, and 1.27 liters/kg, respectively. Total body clearance for the three age groups was 14.2, 12.1, and 7.5 ml/min/kg, respectively. Analysis of variance of these data followed by Duncan's multiple range test indicated a significant decrease in clearance in the aged rats (25-month-old, p less than 0.05). This age-dependent decrease in clearance suggested that digoxin pharmacokinetics could be a significant factor in age-related alterations in digoxin cardiotoxicity in the rat, as it is in humans, and that the Fischer-344 rat could be a useful model for studies of digoxin pharmacokinetic changes with age.

Aging↗
PubMed1985

Binding and structural diversity among high-affinity monoclonal anti-digoxin antibodies.

High-affinity monoclonal antibodies specific for the cardiac glycoside digoxin provide a useful system for the study of structure-function relationships between antibody combining site and specific antigenic determinants. Fifteen high-affinity monoclonal anti-digoxin antibodies were produced when spleen cells from A/J mice immunized with digoxin coupled to human serum albumin (Dig-HSA) were fused with the non-secreting murine myeloma Sp2/0 cell line. Each subcloned hybridoma antibody was analyzed for affinity and specificity for structurally related cardiac glycosides by a radioimmunoassay based on the adsorption of free [3H]digoxin to dextran-coated charcoal. All of the anti-digoxin hybridoma proteins demonstrated high affinity constants ranging from 10(9) to 10(12) M-1. Using seven different analogs of digoxin, binding specificities of the monoclonal antibodies were assessed by inhibition radioimmunoassay. The 15 hybridomas produced from fusions involving five mice could be divided into eight sets on the basis of these binding specificities. Certain antibodies exhibit a preference for the aglycone portion of digoxin, while others are more specific for the tridigitoxose sugar moiety of digoxin. Monoclonal antibody H- and L-chains were subjected to N-terminal amino acid sequence analysis. The antibodies may be divided into several sequence homology sets for both H- and L-chains. In most instances, homologous heavy chains are associated with a set of homologous light chains. Homologous partial sequences, however, do not correlate with similar antigenic specificities and affinities for digoxin. Thus the fine specificity for antigen is not dependent on VH- and VL-encoded sequences alone. These data illustrate the broad diversity of the elicited response to a single hapten, even in inbred mice.

Amino Acid Sequence↗
PubMed1995

Heart rate variability in patients with mild to moderate heart failure: effects of neurohormonal modulation by digoxin and ibopamine. The Dutch Ibopamine Multicenter Trial (DIMT) Study Group.

OBJECTIVES: This study assessed the effects of digoxin and ibopamine on variables of heart rate variability in relation to neurohormonal activation. BACKGROUND: Analysis of heart rate variability can be used to study the autonomic dysfunction that characterizes chronic heart failure. In the Dutch Ibopamine Multicenter Trial, patients with heart failure were found to have increased neurohormonal activation with placebo therapy but not with digoxin and ibopamine therapy. METHODS: We studied 59 patients with mild to moderate heart failure (mean [+/- SEM] age 60 +/- 1 years, mean ejection fraction 0.30 +/- 0.01). Patients were randomized to double-blind treatment with digoxin (0.25 mg [n = 22]), ibopamine (100 mg three times a day [n = 19]) or placebo (n = 18); background therapy consisted of furosemide (up to 80 mg). RESULTS: After 3 months, plasma norepinephrine levels had increased with placebo, whereas they decreased with digoxin (+31 vs. -60 pg/ml, respectively, p < 0.01). With ibopamine, nonsignificant decrease was observed (-27 pg/ml, p = 0.10). All variables of heart rate variability showed a deterioration in the placebo group. With digoxin, the percent differences between successive RR intervals > 50 ms (pNN50) increased (+ 1.7 +/- 0.9%, p < 0.01), along with absolute and normalized high frequency power (+ 40 +/- 33 ms2, p < 0.05 and + 2.4 +/- 1.7%, p < 0.01, respectively). These changes were observed during daytime hours only and were most pronounced in patients with the most impaired baseline heart rate variability. With ibopamine, nonsignificant trends similar to the changes with digoxin were observed. CONCLUSIONS: In patients with early stages of heart failure, digoxin may prevent a progressive deterioration in heart rate variability, whereas ibopamine does not show statistically significant effects. The changes in heart rate variability with digoxin parallel an observed decrease in neurohormonal activation. Digoxin apparently enhances cardiac vagal tone in the setting of neuroendocrine activation.

Aldosterone↗
PubMed2004

Lethal quercetin-digoxin interaction in pigs.

Digoxin is a popular cardiac glycoside with very narrow therapeutic range. Quercetin is an ubiquitous antioxidant flavonoid. Digoxin is a substrate of P-glycoprotein (P-gp), a multi-drug efflux transporter, and quercetin was reported to be a modulator of P-gp. The aim of this study was to investigate the effect of quercetin on the absorption and disposition of digoxin in pigs. Pigs were orally given digoxin (0.02 mg/kg) with and without quercetin in crossover designs. The blood was collected via jugular vein and fluorescence polarization immunoassay was used to determine the serum concentration of digoxin. The pharmacokinetic parameters were calculated using WINNONLIN. The paired Student's t-test was used for statistical comparison. The coadministration of 50 mg/kg quercetin unexpectedly resulted in sudden death of two among three pigs within 30 min after digoxin administration. The coadministration of 40 mg/kg quercetin significantly elevated the Cmax of digoxin by 413% and increased the AUC0-t by 170%. The results indicated that a very serious pharmacokinetic interaction occurred between quercetin and digoxin. The concomitant administration of digoxin and quercetin or quercetin-containing herbs and dietary supplement should be avoided.

Animals↗
PubMed1998

A randomized, double-blind comparison of intravenous diltiazem and digoxin for atrial fibrillation after coronary artery bypass surgery.

BACKGROUND: Atrial fibrillation (AF) after coronary bypass graft surgery may result in hypotension, heart failure symptoms, embolic complications, and prolongation in length of hospital stay (LOHS). The purpose of this study was to determine whether intravenous diltiazem is more effective than digoxin for ventricular rate control in AF after coronary artery bypass graft surgery. A secondary end point was to determine whether ventricular rate control with diltiazem reduces postoperative LOHS compared with digoxin. METHODS AND RESULTS: Patients with AF and ventricular rate > 100 beats/min within 7 days after coronary artery bypass graft surgery were randomly assigned to receive intravenous therapy with diltiazem (n = 20) or digoxin (n = 20). Efficacy was measured with ambulatory electrocardiography (Holter monitoring). Safety was assessed by clinical monitoring and electrocardiographic recording. LOHS was measured from the day of surgery. Data were analyzed with the intention-to-treat principle in all randomly assigned patients. In addition, a separate intention-to-treat analysis was performed excluding patients who spontaneously converted to sinus rhythm. In the analysis of all randomly assigned patients, those who received diltiazem achieved ventricular rate control (> or = 20% decrease in pretreatment ventricular rate) in a mean of 10 +/- 20 (median 2) minutes compared with 352 +/- 312 (median 228) minutes for patients who received digoxin (p < 0.0001). At 2 hours, the proportion of patients who achieved rate control was significantly higher in patients treated with diltiazem (75% vs 35%, p = 0.03). Similarly, at 6 hours, the response rate associated with diltiazem was higher than that in the digoxin group (85% vs 45%, p = 0.02). However, response rates associated with diltiazem and digoxin at 12 and 24 hours were not significantly different. At 24 hours, conversion to sinus rhythm had occurred in 11 of 20 (55%) patients receiving diltiazem and 13 of 20 (65%) patients receiving digoxin (p = 0.75). Results of the analysis of only those patients who remained in AF were similar to those presented above. There was no difference between the diltiazem-treated and digoxin-treated groups in postoperative LOHS (8.6 +/- 2.2 vs 7.7 +/- 2.0 days, respectively, p = 0.43). CONCLUSIONS: Ventricular rate control occurs more rapidly with intravenous diltiazem than digoxin in AF after coronary artery bypass graft surgery. However, 12- and 24-hour response rates and duration of postoperative hospital stay associated with the two drugs are similar.

Aged↗
PubMed2003

Pharmacokinetic and pharmaceutic interaction between digoxin and Cremophor RH40.

BACKGROUND: The pharmacokinetics of digoxin is modulated by the efflux pump P-glycoprotein. Cremophor EL (BASF Aktiengesellschaft, Ludwigshafen, Germany) (polyoxyl 35 castor oil), a castor oil derivative used to improve the solubilization of drugs and vitamins, has been shown to inhibit this membrane transporter in vitro and in vivo. So far, no study in humans has evaluated the effect of Cremophor RH40 (BASF Aktiengesellschaft) (polyoxyl 40 hydrogenated castor oil) on P-glycoprotein. METHODS: A randomized, double-blind, placebo-controlled crossover study in 12 healthy individuals was performed with a single oral dose of 0.5 mg digoxin in a hard gelatin capsule in combination with multiple doses of oral Cremophor RH40 (600 mg 3 times daily) or placebo. A digitized electrocardiogram with 12 standard leads was recorded to assess the pharmacodynamics of digoxin. RESULTS: Cremophor RH40 delayed and enhanced the absorption of digoxin in the first 5 hours after dosing. During Cremophor RH40 administration, digoxin lag time was significantly prolonged compared with placebo (0.53 +/- 0.25 hour versus 0.36 +/- 0.19 hour, P =.04). The peak concentration of digoxin increased by 22%, from 2.21 +/- 0.94 ng/mL to 2.69 +/- 1.28 ng/mL (P =.06). Similarly, the area under the plasma concentration-time curve from 0 to 5 hours significantly increased by 22% (5.23 +/- 1.63 h. ng/mL versus 4.30 +/- 1.12 h. ng/mL, P =.03). Digoxin did not cause a clinically significant change in the dynamic parameters during both periods. CONCLUSION: This study demonstrates a pharmacokinetic and pharmaceutic interaction between the emulgent Cremophor RH40 and digoxin, caused by P-glycoprotein inhibition and prolongation of the dissolution time of digoxin tablets by Cremophor RH40, respectively. Our in vivo study in humans supports the validity of in vitro observations on P-glycoprotein.

Adult↗
PubMed2001

Cilomilast: pharmacokinetic and pharmacodynamic interactions with digoxin.

BACKGROUND: Cilomilast is an orally active, selective phosphodiesterase 4 inhibitor currently in clinical development for the treatment of chronic obstructive pulmonary disease. OBJECTIVE: The purpose of this study was to examine the tolerability and steady-state pharmacokinetics of cilomilast and digoxin when coadministered at standard therapeutic doses in healthy adults. METHODS: In an initial, open-label phase, healthy young adults received cilomilast 15 mg BID for 5 days. After a 7-day washout period, subjects entered a double-blind, crossover phase during which they received oral digoxin (375 microg once daily) for 2 consecutive 14-day periods with no intervening washout period. Cilomilast 15 mg BID or placebo was coadministered during the first 14-day period. Subjects then crossed over to the alternative treatment for the second 14-day period. Blood and urine samples were collected at appropriate times for evaluation of digoxin and cilomilast steady-state pharmacokinetic parameters. The size of the study was sufficient to achieve 90% power to correctly exclude an effect of cilomilast. RESULTS: Twelve of the 16 subjects enrolled completed the study. There were 4 withdrawals--1 due to noncompliance, 1 due to a positive drug screening, and 2 due to adverse events. At steady state, cilomilast 15 mg BID had no significant effect on the steady-state pharmacokinetic parameters of digoxin, with 90% CIs for both primary end points--area under the plasma concentration-time curve (AUC) over a 24-hour dosing interval and minimum plasma concentration--completely contained within the specified interval for equivalence (0.80-1.25). A mean reduction in maximum observed plasma concentration of digoxin of 11% was observed during coadministration with cilomilast, and time to maximum concentration was delayed by a median of 1 hour, suggesting a small reduction in the rate of digoxin absorption. Digoxin did not appear to markedly affect cilomilast steady-state pharmacokinetics. The most frequently reported adverse event was headache. CONCLUSIONS: Cilomilast 15 mg BID had no clinically significant effect on steady-state AUC or on predose trough plasma concentrations of digoxin (375 microg once daily). The steady-state pharmacokinetics of cilomilast 15 mg BID were similar whether administered alone or with digoxin at steady state (375 microg once daily).

Adolescent↗
PubMed2001

Effect of age on mortality, hospitalizations and response to digoxin in patients with heart failure: the DIG study.

OBJECTIVES: This study was designed to determine the effect of increasing age on mortality, hospitalizations and digoxin side effects in patients with heart failure (HF), and to determine whether the effect of digoxin on clinical outcomes varies as a function of age. BACKGROUND: The incidence and prevalence of HF increase with advancing age, but there are limited data on the clinical course and response to specific therapeutic interventions in elderly patients with HF. METHODS: The Digitalis Investigation Group (DIG) study was a prospective, randomized clinical trial involving 7,788 patients with HF randomized to digoxin or placebo and followed for an average of 37 months. In the present analysis, patients were stratified into five age categories: <50 years (n = 841), 50 to 59 years (n = 1,545), 60 to 69 years (n = 2,885), 70 to 79 years (n = 2,092) and > or =80 years (n = 425). Interactions between age and the following clinical outcomes were examined: total mortality, all-cause hospitalizations, HF hospitalizations, the composite of HF death or HF hospitalization, hospitalization for suspected digoxin toxicity and withdrawal from therapy because of side effects. RESULTS: Increasing age was an independent risk factor for total mortality, all-cause hospitalization, HF hospitalization, HF death or hospital admission, hospitalization for suspected digoxin toxicity and withdrawal from digoxin therapy (all p < 0.001). However, there were no significant interactions between age and digoxin treatment with respect to any of the major clinical end points. CONCLUSIONS: Increasing age is associated with progressively worse clinical outcomes in patients with HF. However, the beneficial effects of digoxin in reducing all-cause admissions, HF admissions, and HF death or hospitalization are independent of age. Thus, digoxin remains a useful agent for the adjunctive treatment of HF due to impaired left ventricular systolic function in patients of all ages.

Age Factors↗
PubMed1985

Pharmacokinetic evaluation of the digoxin-amiodarone interaction.

Amiodarone is known to raise serum digoxin levels. This study was designed to evaluate the pharmacokinetic basis of this interaction in 10 normal subjects. The pharmacokinetic variables for digoxin were determined after a 1.0 mg intravenous dose of digoxin in each subject, before and after oral amiodarone, 400 mg daily for 3 weeks. During amiodarone administration, systemic clearance of digoxin was reduced from 234 +/- 72 ml/min (mean +/- standard deviation) to 172 +/- 33 ml/min (p less than 0.01). This was due to reductions in both renal clearance (from 105 +/- 39 to 84 +/- 15 ml/min) (p less than 0.05) and nonrenal clearance (from 130 +/- 38 to 88 +/- 20 ml/min) (p less than 0.01). Digoxin half-life of elimination was prolonged from 34 +/- 13 to 40 +/- 16 hours (p less than 0.05). Digoxin volume of distribution was not significantly changed. Amiodarone caused a three- to fivefold increase in serum reverse triiodothyronine levels, but changes in thyroid function were not quantitatively related to the changes in digoxin pharmacokinetics. These alterations in digoxin pharmacokinetics produced by amiodarone explain the increase in serum digoxin level that has been observed when this drug combination has been used clinically.

Adult↗
PubMed1985

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.

Antacids↗
PubMed1996

Value of digoxin in heart failure and sinus rhythm: new features of an old drug?

Digoxin has been a controversial drug since its introduction >200 years ago. Although its efficacy in patients with heart failure and atrial fibrillation is clear, its value in patients with heart failure and sinus rhythm has often been questioned. In the 1980s, reports of some large-scale trials indicated that digoxin, with or without vasodilators or angiotensin-converting enzyme inhibitors, reduced signs and symptoms of congestive heart failure and improved exercise tolerance. This beneficial influence was mainly found in patients with more advanced heart failure and dilated ventricles, whereas the effect in those with mild disease appeared to be less pronounced. In the last few years, new data have shown that digoxin may also have clinical value in mild heart failure, either when used in combination with other drugs or when administered alone. As neurohumoral activation has increasingly been recognized to be a contributing factor in the disease progression of chronic heart failure, the modulating effects of digoxin on neurohumoral and autonomic status have received more attention. Also, there is evidence that relatively low doses of digoxin may be at least as effective as higher doses and have a lower incidence of side effects. Further, the recognition that the use of digoxin too early after myocardial infarction may be harmful and the development of other drugs, in particular angiotensin-converting enzyme inhibitors, have obviously changed the place of digoxin in the treatment of chronic heart failure. The large-scale survival trial by the Digitalis Investigators Group (DIG), whose preliminary results have recently been presented, has shown that although digoxin has a neutral effect on total mortality during long-term treatment, it reduces the number of hospital admissions and deaths due to worsening heart failure. The potentially new features of the old drug digoxin are discussed in this review.

Anti-Arrhythmia Agents↗
PubMed1996

Physiologic pharmacokinetic modeling of gastrointestinal blood flow as a rate-limiting step in the oral absorption of digoxin: implications for patients with congestive heart failure receiving epoprostenol.

A previously validated physiologically based pharmacokinetic model was used to examine whether epoprostenol-induced increases in gastrointestinal blood flow (Qg) could alter digoxin systemic bioavailability to a clinically significant extent in severe congestive heart failure (CHF) patients. A series of simulations was conducted in which the influences of apparent gut tissue-to-plasma partition coefficient (Kg) and Qg on digoxin bioavailability were evaluated. Since epoprostenol also increases blood flow to the liver and kidneys, the effect of concurrent increases in regional blood flow to these organs on digoxin bioavailability also was evaluated. A range of Qg was studied from 25 L/h (assumed mesenteric arterial flow in CHF) to 65 L/h (portal venous flow in normal adults), and the area under the simulated digoxin concentration-time curve was used to calculate absolute digoxin bioavailability in each case. Simulations were conducted at a range of Kg from 1 to 50 (physiologically relevant range 5-25). At low values of Kg, the influence of changes in Qg on digoxin bioavailability was minimal. However, as apparent distribution into gut tissue increased (consistent with visceral congestion), the effect of changes in Qg was more substantial. In the physiologically relevant range of Kg, 40-160% increases in Qg were associated with approximately 6-40% increases in digoxin bioavailability. Therefore, the decrease in digoxin oral clearance previously observed in CHF patients receiving epoprostenol may be ascribed to increases in digoxin bioavailability, secondary to epoprostenol-induced increases in Qg.

Adult↗
PubMed2002

Organic anion transporter oatp2-mediated interaction between digoxin and amiodarone in the rat liver.

PURPOSE: The interaction between amiodarone and digoxin has been known to increase serum concentrations of digoxin in humans and rats. In this study, we assessed the molecular mechanism(s) of that drug interaction, focusing on digoxin transport mediated by P-glycoprotein (Pgp) and by rat liver organic anion transporter (oatp2). METHODS: Digoxin transport by Pgp and oatp2 was assessed using Pgp-overexpressing transfectant LLC-GA5-COL150 monolayers and oatp2-expressing Xenopus oocytes, respectively. The digoxin uptake into the isolated rat hepatocytes was also examined. RESULTS: Amiodarone (10 microM) inhibited slightly the transcellular transport of digoxin in LLC-GA5-COL150 monolayers, whereas itraconazole (10 microM), a potent Pgp inhibitor, markedly blocked the transport. The digoxin uptake by the isolated rat hepatocytes and by the oatp2-expressing Xenopus oocytes was decreased markedly in the presence of amiodarone but not in the presence of itraconazole. In addition, amiodarone inhibited the oatp2-mediated digoxin uptake in a competitive manner with an apparent inhibition constant value of 1.8 microM. CONCLUSION: These findings suggest that rat oatp2 rather than Pgp may be one of the interaction sites for digoxin and amiodarone in the liver.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1981

Digoxin bioavailability during quinidine administration.

Digoxin serum concentration rises in the presence of quinidine. To determine whether quinidine alters digoxin bioavailability, six subjects received 1.0 mg of digoxin intravenously alone and by mouth on alternate weeks during steady-state oral quinidine administration. The area under the digoxin concentration:time curves (AUC) and the amount of digoxin excreted in the urine (Xxu) were determined for the 96 hr after each of the four experiments. Values for digoxin bioavailability relative to the corresponding intravenous study in the absence and presence of quinidine were (+/- S.D.) 73.5 +/- 8.6% and 79.5 +/- 22.6% (P greater than 0.05) for serum and 69.8 +/- 6.8% and 70.2 +/- 10.5% (P greater than 0.05) for urine. There was no difference in the steady-state quinidine serum concentration during the 4 days after intravenous and oral digoxin. We conclude that quinidine does not alter digoxin bioavailability and therefore that altered absorption does not explain the rise in digoxin serum concentration in the presence of quinidine.

Adult↗