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PubMed2003

Dipyridamole enhances digoxin bioavailability via P-glycoprotein inhibition.

BACKGROUND: On the basis of in vitro studies indicating that dipyridamole is an inhibitor for the MDR1 efflux membrane transporter P-glycoprotein, we postulated that dipyridamole could increase the bioavailability of digoxin, a P-glycoprotein substrate. OBJECTIVES: The main objective was to determine whether dipyridamole alters the bioavailability of digoxin. The secondary objective was to determine whether the magnitude of the pharmacokinetic interaction was influenced by MDR1 genetic polymorphism in exon 26 (C3435T). MATERIAL AND METHODS: (1) The effect of dipyridamole on in vitro P-glycoprotein-mediated, polarized transport of tritium-labeled digoxin was investigated in Caco-2 cell monolayers. (2) Twelve healthy volunteers participated in this open, randomized, 2-period crossover study, in which the effects of dipyridamole (300 mg/d for 3 days) versus placebo on the pharmacokinetics of a single oral dose of digoxin (0.5 mg) were compared. MDR1 genotyping (exon 26, C3435T) was determined before the study to include 6 homozygous CC and 6 homozygous TT subjects. RESULTS: Dipyridamole inhibited [(3)H]digoxin transport in Caco-2 cells with a 50% inhibitory concentration value of 1.5 +/- 1.5 micromol/L. We observed a 20% and 13% increase in digoxin area under the plasma concentration-time curve (AUC) from 0 to 4 hours and AUC from 0 to 24 hours (P <.05), respectively, during dipyridamole administration, which was consecutive to an increase in digoxin absorption. Digoxin AUC from 0 to 4 hours and AUC from 0 to 24 hours were significantly higher among subjects harboring the TT compared with the CC MDR1 genotype: 7.5 +/- 1.2 ng x h x mL(-1) versus 6.1 +/- 0.8 ng x h x mL(-1) and 20.2 +/- 2.1 ng x h x mL(-1) versus 16.8 +/- 1.7 ng x h x mL(-1), respectively (P <.05). Digoxin pharmacokinetic modifications during the dipyridamole period were similar in both genotypes. CONCLUSION: Dipyridamole is an in vitro and in vivo P-glycoprotein inhibitor that increases intestinal digoxin absorption and digoxin plasma concentrations. In light of the modest changes in digoxin pharmacokinetics in the presence of dipyridamole, this drug interaction is probably clinically irrelevant.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Are the sympathetic neural effects of digoxin and quinidine involved in their action on cardiac rhythm?

This study was initiated to determine if ventricular arrhythmia induced by digoxin was associated with a nonuniform neural discharge in the cardiac sympathetic postganglionic fibers. In addition, splanchnic neural discharge was monitored to explore the role of adrenal medullary catecholamines in digoxin-induced arrhythmia. Experiments were performed to ascertain whether the antiarrhythmic effects of quinidine in digoxin-induced arrhythmias were related to an action on cardiac sympathetic neural discharge induced by digoxin. All cats were anesthetized with alpha-chloralose and given atropine; some were pretreated with quinidine (10 or 20 mg/kg i.v. 15 min before digoxin). Digoxin was given every 15 min until death; the first three doses were 50 micrograms/kg i.v., and all subsequent doses were 25 micrograms/kg. The mean +/- SE time to arrhythmia was 32 +/- 4 min (n = 16) and was significantly increased only after 20 mg/kg quinidine (64 +/- 7 min; p less than 0.001). Mean +/- SE time to death was also increased from 74 +/- 4 to 98 +/- 7 min (p less than 0.001). Postganglionic cardiac sympathetic neural discharge before digoxin-induced arrhythmia was depressed. Of the 28 nerves monitored in 16 animals receiving digoxin, in the minute before development of arrhythmia, 22 nerves were depressed, 3 were increased, and 3 showed no change when compared with the predigoxin control. Following this depression of neural discharge, arrhythmia developed, and the neural discharge began to rise, eventually increasing above control levels. During this time the variability of the neural discharge increased greatly, as evidenced by large SE values, so that the mean values were not significantly different from control levels. Splanchnic neural discharge (n = 9) progressively decreased, reaching 66% of control values after the third injection of digoxin; the discharge then began to increase gradually toward control levels in the next 10 min and arrhythmia developed. The data indicate that the arrhythmias caused by digoxin are not associated with the development of nonuniform discharge patterns in the cardiac sympathetic nerves. Furthermore, action on the splanchnic nerve discharge is not involved in the arrhythmogenic effects of digoxin. Pretreatment with quinidine, 20 mg/kg, decreased both splanchnic and post-ganglionic cardiac sympathetic neural discharge, arterial blood pressure, and heart rate. Although quinidine, 20 mg/kg, increased the time to arrhythmia induced by digoxin, the depression of postganglionic cardiac or splanchnic neural discharge did not seem to be a major component of the antiarrhythmic effect of quinidine.

Animals↗
PubMed1997

Itraconazole decreases renal clearance of digoxin.

Itraconazole strongly interacts with some drugs metabolized by cytochrome P450 3A4, for example, felodipine and lovastatin, by inhibiting their metabolism. A concomitant use of itraconazole increases the serum concentrations of digoxin, although digoxin is excreted mainly unchanged in urine. To reveal the mechanism of the itraconazole-digoxin interaction, the effect of itraconazole on the serum concentrations and urinary excretion of digoxin was studied. Ten healthy volunteers in a double-blind, randomized, two-phase crossover study received either 200 mg itraconazole or placebo orally once a day for 5 days. On day 3, each volunteer ingested a single 0.5-mg oral dose of digoxin. The serum concentrations of digoxin and its excretion into urine as well as plasma concentrations of itraconazole were determined up to 72 hours after dosing. The mean area under the serum digoxin concentration-time curve, AUC(0-72), was approximately 50% higher (P < 0.001) during the itraconazole phase than during the placebo phase. In addition, the renal clearance of digoxin decreased about 20% (P < 0.01) by itraconazole. The increases in digoxin Cmax and T(1/2) by itraconazole were not statistically significant. The decreased renal clearance of digoxin during the itraconazole phase partially explains increased concentrations of digoxin during their concomitant use and may be caused by the inhibition of P-glycoprotein-mediated digoxin secretion in the renal tubular cells.

Administration, Oral↗
PubMed1998

Bidirectional (positive/negative) interference in a digoxin immunoassay: importance of antibody specificity.

The importance of high specificity in immunoassays used in therapeutic monitoring is highlighted by a case study in which therapeutic-to-toxic borderline digoxin levels were measured by a digoxin immunoassay in the serum sample from a patient administered digitoxin rather than digoxin. The sample, mistakenly sent to the laboratory for digoxin analysis, gave discordant results in three digoxin immunoassays: 1.99 and 0.79 ng/ml in assays using polyclonal antibodies (fluorescence-polarization immunoassay and microparticle enzyme immunoassay, respectively), and <0.1 ng/ml in a chemiluminescent immunoassay using more specific monoclonal antibody. The presence of digitoxin (approximately 40 ng/ml) in the sample was confirmed by three different digitoxin immunoassays. Based on these results, the interference of different levels of digitoxin was studied in the presence of 0, 0.85, 1.9, and 4.7 ng/ml digoxin in all three digoxin assays. The chemiluminescent assay showed no significant interference. The fluorescence-polarization immunoassay showed positive interference in all cases; however, the microparticle enzyme immunoassay showed a bidirectional interference: a positive interference observed at digoxin level <1.8 ng/ml, changing to a negative interference at higher digoxin concentrations. The authors conclude that in countries such as Germany, where both digoxin and digitoxin may be prescribed, caution should be used to interpret digoxin immunoassay results. Digoxin assays, with cross-reactivity to digitoxin <0.1% should be used.

Antibody Specificity↗
PubMed2004

Rapid detection of oleander poisoning using digoxin immunoassays: comparison of five assays.

Oleander is an ornamental shrub that grows in the United States, Australia, India, Sri Lanka, China, and other parts of the world. All parts of the plant are poisonous because the presence of cardiac glycoside oleandrin. Despite its toxicity, oleander extract is used in folk medicines. Because of its structural similarity, oleandrin cross-reacts with the fluorescence polarization immunoassay (FPIA) for digoxin. We studied the potential of detecting oleandrin in serum using 5 common digoxin immunoassays (FPIA, MEIA, both from Abbott; Beckman digoxin assay on Synchron LX, Chemiluminescent assay, CLIA from Bayer Diagnostics) and a recently FDA-approved turbidimetric assay on the ADVIA 1650 analyzer (Bayer). Aliquots of drug-free and digoxin-like immunoreactive substances (DLIS)-free serum pools were supplemented with ethanol extract of oleander leaves or oleandrin (Sigma Chemicals) in amounts expected in vivo after severe overdose. We observed significant apparent digoxin concentration with FPIA, Beckman, and the new turbidimetric assay (1 mL drug-free serum supplemented with 5.0 microL of oleander extract: apparent digoxin 2.36 ng/mL by the FPIA, 0.32 ng/mL by the MEIA, 0.93 ng/mL by the Beckman, 0.82 ng/mL by the new turbidimetric assay). The CLIA showed no cross-reactivity. Similar observations were made when serum pools were supplemented with oleandrin. Because cross reactivity should be tested in the presence of the primary analyte, we supplemented serum pools prepared from patients receiving digoxin with oleander extract or oleandrin. The measured digoxin concentrations were falsely elevated with the FPIA, Beckman, and turbidimetric assays, the highest false elevation being observed with the FPIA. Surprisingly, apparent digoxin concentrations were falsely lowered when MEIA was used. Digibind neutralizes free apparent digoxin concentration in vitro in serum pools supplemented with oleander extract, and this effect can be measured by the FPIA. We conclude that FPIA is most sensitive to detect the presence of oleander in serum. In contrast, the CLIA (no cross-reactivity) should be used for monitoring digoxin in a patient receiving digoxin and self-medicated with a herbal remedy containing oleander.

Confidence Intervals↗
PubMed1980

The effect of quinidine on digoxin kinetics in cardiac patients.

The pharmacokinetics of digoxin was studied in 11 subjects before and during quinidine treatment. Renal clearances of digoxin and creatinine were calculated from plasma concentrations and urinary excretions of digoxin and creatinine in subjects on long-term digoxin treatment. The investigations were repeated in the same subjects during administration of quinidine. Renal clearance of digoxin decreased, while plasma concentration of digoxin and renal excretion of digoxin increased in the presence of quididine, indicating substantial changes of digoxin kinetics, induced by quinidine. The reduction in renal clearance of digoxin may be due to a specific inhibition of tubular secretion of digoxin. The considerable rise of the plasma digoxin level and the increased excretion of digoxin support the assumption of a major extrarenal mechanism of interaction.

Aged↗
PubMed1994

Effect of physical activity on the day-to-day variation in serum digoxin concentration.

Physical exercise has been found to increase digoxin binding in working skeletal muscle along with a concomitant decrease in serum digoxin concentration. In a recent study on healthy volunteers, moderate physical activity during maintenance digoxin treatment was shown to decrease the renal excretion of digoxin secondary to this redistribution of the drug, thereby affecting the body content of digoxin. In the present study the influence of changes in everyday physical activities, carried out during a 10-h period after ingestion of the daily maintenance digoxin dose, on the steady-state serum digoxin concentration (24 h after the last dose) was studied in 10 digoxin-treated outpatients (61-81 years of age). Compared to normal daily activity, complete bed rest for 10 h after ingestion of the maintenance dose did not affect the steady-state serum digoxin concentration. The lack of such an influence may be explained either by a low degree of everyday physical activity in the investigated patients or to a compensatory increase in the renal excretion of digoxin during the night preceding the serum digoxin measurement. Thus, standardization of physical activity 1-2 h before blood sampling is adequate when analysing the serum digoxin concentration in elderly outpatients.

Administration, Oral↗
PubMed1992

Activation of glycolysis with isoproterenol but not digoxin reverses chronic alcohol depression in hamster hearts.

The purpose of this study was to confirm that an agent, which increases diastolic [Ca2+]i, namely digoxin, depresses cardiac performance, mitochondrial activity, and glycolysis in chronic alcohol-treated and myopathic hearts, and that an agent, which lowers diastolic [Ca2+]i, namely isoproterenol, activates cardiac performance, mitochondrial activity, and glycolysis in these animals. Energy levels, glycolysis, mitochondrial activity, hemodynamics, and cAMP were studied in isolated hearts from three groups of animals, i.e., 9-month control hamsters, hamsters given 50% alcohol until 9 months of age, and 6-month-old cardiomyopathic hamsters in heart failure. Isolated hearts were perfused with either a control medium, a medium containing isoproterenol, digoxin, or digoxin + isoproterenol. Measurement of phosphomonoester sugars, and glucose-6-phosphate, were used to assess glycolytic activity. Oxygen consumption was used to analyze mitochondrial activity. All hearts perfused with either isoproterenol or isoproterenol + digoxin showed an increase in developed pressure, rate-pressure-product, and a decrease in end-diastolic pressure. Isoproterenol activated mitochondrial activity and glycolysis in hearts from myopathic and chronic alcohol hamsters. Based on 31P-NMR studies, isoproterenol or isoproterenol + digoxin improved the over-all energy state of hearts from cardiomyopathic hamsters, but not hearts from control and chronic alcohol hamsters. Digoxin alone augmented the rate-pressure-product and oxygen consumption in control hearts but not hearts from myopathic and chronic alcohol hamsters. Digoxin caused an increase in end-diastolic pressure in myopathic and chronic alcohol hearts but not control hearts. Digoxin depressed glycolysis and worsened the energy state in hearts from cardiomyopathic and chronic alcohol hamsters, but not hearts from control hamsters. In conclusion digoxin, but not isoproterenol nor isoproterenol + digoxin, depressed cardiac performance and glycolysis as well as high energy phosphates in cardiomyopathic and chronic alcohol hearts. Isoproterenol added to digoxin negated the adverse effects of digoxin in cardiomyopathic and chronic alcohol hearts.

Animals↗
PubMed1995

Quinidine administration increases steady state serum digoxin concentration in horses.

The aim of this study was to determine if quinidine administration increases steady state serum digoxin concentration in horses. Digoxin (0.01 mg/kg q. 12 h per os) was administered to 6 horses for 7 days. Steady state was confirmed by identifying statistically indistinguishable peak and trough serum digoxin concentrations on Days 4, 5, and 6. On Day 6, serum digoxin concentration was measured at baseline and 0.25, 0.5, 1, 2, 4, 6, 8 and 12 h after digoxin administration. On Day 7, quinidine (20 g at baseline and 10 g at 2, 4 and 6 h) was administered per os and serum digoxin concentration was measured at the same time intervals. Creatinine and renal digoxin clearances were measured on Days 6 and 7. Results indicated that there was approximately a doubling of serum digoxin concentration (from mean +/- s.d. 2.57 +/- 0.96 ng/ml at baseline to 4.28 +/- 1.31 at 15 min and 5.98 +/- 1.21 ng/ml at 30 min) after starting the administration of quinidine. This elevation persisted for the 12 h after starting quinidine administration. Renal digoxin and endogenous creatinine clearances decreased but the decrease in digoxin clearance was greater. Serum quinidine concentration achieved the therapeutic range (2-6 micrograms/ml) in 5 of the 6 horses. In summary, similar to findings in other species, quinidine administration increases steady state serum digoxin concentration in horses and this occurs, at least in part, due to a decrease in renal digoxin clearance. Some of the decrease in renal clearance is due to decreased glomerular filtration which is dissimilar to findings in other species.

Animals↗
PubMed1999

The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin.

Recent data point to the contribution of P-glycoprotein (P-gp) to digoxin elimination. On the basis of clinical observations of patients in whom digoxin levels decreased considerably when treated with rifampin, we hypothesized that concomitant rifampin therapy may affect digoxin disposition in humans by induction of P-gp. We compared single-dose (1 mg oral and 1 mg intravenous) pharmacokinetics of digoxin before and after coadministration of rifampin (600 mg/d for 10 days) in 8 healthy volunteers. Duodenal biopsies were obtained from each volunteer before and after administration of rifampin. The area under the plasma concentration time curve (AUC) of oral digoxin was significantly lower during rifampin treatment; the effect was less pronounced after intravenous administration of digoxin. Renal clearance and half-life of digoxin were not altered by rifampin. Rifampin treatment increased intestinal P-gp content 3.5 +/- 2.1-fold, which correlated with the AUC after oral digoxin but not after intravenous digoxin. P-gp is a determinant of the disposition of digoxin. Concomitant administration of rifampin reduced digoxin plasma concentrations substantially after oral administration but to a lesser extent after intravenous administration. The rifampin-digoxin interaction appears to occur largely at the level of the intestine. Therefore, induction of intestinal P-gp could explain this new type of drug-drug interaction.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Atorvastatin coadministration may increase digoxin concentrations by inhibition of intestinal P-glycoprotein-mediated secretion.

The effect of atovarstatin on digoxin pharmacokinetics was assessed in 24 healthy volunteers in two studies. Subjects received 0.25 mg digoxin daily for 20 days, administered alone for the first 10 days and concomitantly with 10 mg or 80 mg atorvastatin for the last 10 days. Mean steady-state plasma digoxin concentrations were unchanged by administration of 10 mg atorvastatin. Mean steady-state plasma digoxin concentrations following administration of digoxin with 80 mg atorvastatin were slightly higher than concentrations following administration of digoxin alone, resulting in 20% and 15% higher Cmax and AUC(0-24) values, respectively. Since tmax and renal clearance were not significantly affected, the results are consistent with an increase in the extent of digoxin absorption in the presence of atorvastatin. Digoxin is known to undergo intestinal secretion mediated by P-glycoprotein. Since atorvastatin is a CYP3A4 substrate and many CYP3A4 substrates are also substrates for P-glycoprotein transport, the influence of atorvastatin and its metabolites on P-glycoprotein-mediated digoxin transport in monolayers of the human colon carcinoma (Caco-2) cell line was investigated. In this model system, atorvastatin exhibited efflux or secretion kinetics with a K(m) of 110 microM. Atorvastatin (100 microM) inhibited digoxin secretion (transport from the basolateral to apical aspect of the monolayer) by 58%, equivalent to the extent of inhibition observed with verapamil, a known inhibitor of P-glycoprotein transport. Thus, the increase in steady-state digoxin concentrations produced by 80 mg atorvastatin coadministration may result from inhibition of digoxin secretion into the intestinal lumen.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Digoxin toxicity secondary to clarithromycin therapy.

OBJECTIVE: To report a case of digoxin toxicity thought to be secondary to clarithromycin therapy. CASE SUMMARY: A 78-year-old white woman with congestive heart failure taking digoxin 0.25 mg po qd presented to our hospital with nausea, vomiting, and diarrhea. She had taken clarithromycin 500 mg po bid for 3 days, and a serum digoxin concentration obtained the day of admission was 4.4 mug/L. An electrocardiogram (ECG) done on admission revealed ST segment changes consistent with digoxin effect and later asymptomatic, nonsustained ventricular tachycardia (NSVT). Clarithromycin was discontinued and digoxin was withheld at admission, resulting in the resolution of symptoms, ECG abnormalities, and NSVT on day 3 of hospitalization. On day 5 her serum digoxin concentration was 1.5 micrograms/L and digoxin therapy was reinstituted at a dose of 0.125 mg/d po. DISCUSSION: This is the fourth published case implicating clarithromycin as the cause of digoxin toxicity. This interaction is most likely due to clarithromycin eradication of digoxin-metabolizing gut flora, thereby increasing digoxin bioavailability. CONCLUSIONS: Approximately 10% of patients are thought to be extensive presystemic metabolizers of digoxin and may therefore be most susceptible to a drug interaction with clarithromycin. Serum digoxin concentrations in such patients should be monitored closely during clarithromycin therapy.

Aged↗
PubMed1997

Clarithromycin-induced digoxin intoxication.

OBJECTIVE: To report a case of clarithromycin-induced digoxin intoxication. CASE SUMMARY: A 78-year-old white man with ischemic cardiomyopathy and chronic renal insufficiency was admitted 4 days after being prescribed clarithromycin for a suspected episode of bronchitis. He reported weakness, asthenia, and gastrointestinal symptoms; the digoxin serum concentration was measured at 3.89 ng/mL. The patient recovered uneventfully after digoxin and clarithromycin were discontinued. DISCUSSION: Erythromycin frequently interacts with other drugs that are also metabolized by the CYP3A4 isoenzyme. However, erythromycin is hypothesized to interact with digoxin by inhibiting Eubacterium lentum, which is a normal inhabitant of the human gut and is responsible for intestinal metabolism of digoxin in 10% of patients. Since clarithromycin shares a comparable antibacterial spectrum with erythromycin, the possibility of a drug interaction with digoxin remains. Only four cases of clarithromycin interacting with digoxin have been reported to date. Clinically, this interaction may have been more obvious because of our patient's moderate renal dysfunction and serum digoxin concentrations in the upper therapeutic range prior to clarithromycin initiation. Other causes for digoxin intoxication could not be identified. CONCLUSIONS: Clarithromycin may inhibit the growth of E. lentum, which can lead to an increase in digoxin bioavailability and blood concentrations in patients in whom this intestinal metabolic pathway is present. Patients at risk include those with renal dysfunction, with serum concentrations in the upper therapeutic range, or with measured digoxin concentrations that are much lower than predicted by pharmacokinetic calculations. For these patients, appropriate therapy includes the selection of an alternative, noninteracting antibiotic or, if this is not possible, a temporary reduction of digoxin dosage.

Aged↗
PubMed1984

Endogenous digoxin-immunoreactive substance in human pregnancies.

We report the presence of an immunoreactive digoxin-like substance in blood from third trimester pregnant women. The sera from 51 women in the third trimester of pregnancy were analyzed by 4 commercially available digoxin RIAs. None of these patients was receiving digoxin. Digoxin immunoreactivity was detected in all patients by 3 of 4 assays. The measured values, in nanograms per ml digoxin equivalent, were (mean +/- SD): method A, 0.27 +/- 0.05; method B, 0.28 +/- 0.07; method C, 0.01 +/- 0.01; and method D, 0.15 +/- 0.06. Method B measured values greater than 0.50 ng/ml in sera from 5 patients. Digoxin immunoactivity was not detectable 24 h postpartum, suggesting a half-life in serum of 6 h or less. Exogenous digoxin added to these serum samples resulted in quantitatively additive increments above the endogenous measured levels. Three of 4 digoxin RIAs did not distinguish between true digoxin and the endogenous substance present in the sera of third-trimester pregnant patients. Preliminary evidence suggests that the endogenous digoxin immunoactivity is not due to elevation of levels of major known steroids in the blood of these women. Clinical management of women requiring digoxin therapy during pregnancy, therefore, is complicated by the inability to assume the same therapeutic range of digoxin in serum during the third trimester of pregnancy as in adult nonpregnant individuals.

Adult↗
PubMed2006

Effect of plantain on therapeutic drug monitoring of digoxin and thirteen other common drugs.

INTRODUCTION: Plantain, a herbal remedy, has been reported to interfere with therapeutic drug monitoring of digoxin. We evaluated three commercially available plantain products for potential interference with therapeutic drug monitoring of digoxin and 13 other common drugs. METHOD: Dry content of plantain capsule or plantain leaf was extracted with either methanol or ethanol:water (60:40 by volume), added to drug-free serum and apparent digoxin was measured by both fluorescence polarization immunoassay and microparticle enzyme immunoassay. Using immunoassays, we also measured apparent concentrations of 13 other drugs (tobramycin, procainamide, tricyclic antidepressants, quinidine, carbamazepine, phenytoin, theophylline, valproic acid, amikacin, gentamycin, phenobarbital, salicylate and acetaminophen [paracetamol]) due to the presence of plantain. In separate experiments, a serum pool prepared from patients receiving digoxin was further supplemented with plantain and observed digoxin values were compared with original digoxin concentration. The presence of any cardiac glycoside in plantain was also investigated using thin layer chromatography (TLC). RESULTS: We observed no apparent digoxin in the presence of plantain in serum. Moreover, when aliquots of digoxin serum pool were supplemented with various amounts of plantain, the observed digoxin concentrations in the presence of plantain compared well with original digoxin concentration. TLC analysis did not show the presence of either digoxin or digitoxin in plantain products studied. Moreover, plantain did not affect immunoassay results of the 13 other drugs studied. CONCLUSIONS: The plantain products studied did not interfere with therapeutic drug monitoring of digoxin as well as 13 other commonly monitored drugs.

Cardiac Glycosides↗
PubMed2000

Differential regulation of the sodium pump alpha-subunit isoform gene by ouabain and digoxin in tissues of rats.

The effects of ouabain and digoxin on both the systolic blood pressure (SBP) and sodium pump alpha-subunit expression in some tissues of rats were compared. Normal rats were injected with ouabain, digoxin, and normal saline (NS), respectively, everyday, and indirect SBP was recorded once a week. Six weeks later, all the rats were killed, and sodium pump alpha1-, alpha2-, and alpha3-subunit mRNA levels were detected in the myocardium, kidney, adrenal gland, aortic smooth muscle, and hypothalamus by the RT-PCR method. The results showed that the SBP of rats infused with ouabain increased significantly at the end of week 6, while no difference in SBP was found between the digoxin and NS groups. The effects of ouabain and digoxin on sodium pump alpha-subunit isoform expression were also different. Myocardium: both ouabain and digoxin stimulated expression of the alpha3-isoform whereas alpha2 was unchanged. Levels of the alpha1 isoform decreased significantly in the ouabain group and decreased slightly in the digoxin group, respectively. Kidney: digoxin had the same effects as ouabain. alpha1 levels increased, but those of alpha2 and alpha3 remained unchanged. Adrenal gland: alpha2 and alpha3 levels increased, but those of alpha1 decreased in the ouabain group. alpha1 and alpha3 levels increased and those of alpha2 remained unchanged in the digoxin group. Aortic smooth muscle: both ouabain and digoxin increased alpha1 and alpha3 expression. alpha2 levels decreased in the digoxin group but remained unchanged in the ouabain group. Hypothalamus: both ouabain and digoxin stimulated alpha1 expression, while alpha2 and alpha3 levels remained unchanged. The results of this study have shown that ouabain and digoxin have the different effects on both the systolic blood pressure and expression of sodium pump alpha-subunit isoforms in some tissues in rats. Further studies on the expression of sodium pump alpha-subunit isoforms might be helpful for the understanding of the physiological role of endogenous ouabain and the molecular mechanisms involved in the pathogenesis of hypertension.

Animals↗
PubMed2005

Interactions between clarithromycin and digoxin in patients with end-stage renal disease.

OBJECTIVE: To report a significant increase in the serum levels of digoxin associated with the use of clarithromycin in six patients undergoing renal replacement therapy. CASE SUMMARY: All six patients were males with end-stage renal disease and in need of renal replacement therapy. Four patients were anuric. The mean age was 78.8 +/- 5.8 (66-83) years. All patients except one, who was treated by hemofiltration, were treated by hemodialysis. All patients except one, who had been treated with metildigoxin (0.35 mg/week), were also taking digoxin (0.375 mg/week). Clarithromycin was administered at a dose of 200-400 mg/day for the treatment of bronchitis in all patients. The concomitant administration of clarithromycin increased serum digoxin levels from 1.8-4.0-fold in all cases. In two of six cases, a high probability of digoxin intoxication and suspicion of digoxin intoxication was evident. In three of six cases, serum digoxin levels increased within 12 days after the co-administration of clarithromycin, while in the other three cases, serum digoxin levels were increased 53-190 days after the administration of clarithromycin. CONCLUSION: The simultaneous administration of clarithromycin caused an increase in digoxin levels in six patients undergoing renal replacement therapy. The increase in the serum digoxin can be attributed to the inhibition of P-glycoprotein in the intestine and/or bile capillary rather than the kidney by clarithromycin since renal function was dramatically impaired, and four of the patients were anuric. The issue of why serum digoxin levels were increased so late in three patients undergoing renal replacement is unclear. However, this interaction seemed to be clinically significant even in ESRD patients, whose renal function was highly impaired. The simultaneous use of digoxin and clarithromycin should be avoided even in patients undergoing renal replacement therapy whose renal function is impaired, since digoxin levels may increase unexpectedly.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Non-pretreatment digoxin assays and developments in immunoanalyzers.

OBJECTIVE: The performance of a new, non-pretreatment digoxin assay for the Abbott IMx analyzer (Abbott Park IL) was evaluated to determine its reliability and suitability for routine clinical use. The operational characteristics of 1st, 2nd and 3rd generation immunoanalyzers are compared and contrasted. DESIGN: Within-run and day-to-day precision of the assay was determined, as well as its limit of detection. The effect of digoxin-like immunoreactive factors and carryover were evaluated. Serum from patients receiving digoxin was analyzed using the Dade Stratus II (Miami FL) digoxin test as the reference method and the IMx digoxin test as the comparison method. SETTING: An independent reference laboratory specializing in serving long-term care facilities. PATIENT POPULATION: Specimens were analyzed from geriatric patients in long-term care facilities who receive digoxin as a therapeutic drug for cardiac arrhythmias. Specimens were also tested from individuals in this same population, not receiving digoxin but demonstrating the presence of digoxin-like immunoreactive factors. MAIN OUTCOME MEASURE: Comparability of results from a new nonpretreatment digoxin with the standard digoxin assay (Stratus II) was used to determine the suitability of the new test for routine clinical use. RESULTS: The limit of detection is 0.27 ng/mL; day-to-day precision ranges from 3.4% CV to 5.9% CV. Linear regression analysis generated the following equation: IMx = 0.968 Stratus + 0.1043, r = 0.9776, n = 237. No significant interference from digitoxin-like immunoreactive factors was noted. CONCLUSION: The IMx nonpretreatment digoxin assay's performance matches the manufacturer's claims, compares favorably with another common automated digoxin test, and is suitable for routine clinical use.

Aged↗