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PubMed1981

The assessment of the intrasubject variability in digoxin absorption in man from two oral dosage forms.

The reproducibility of drug absorption within a given subject as well as the evaluation of bioavailability of two digoxin dosage forms were studied. The data showed (a) a higher initial plasma digoxin concentration after the soft elastic gelatin (SEG) capsule; (b) a more irregular absorption after the tablet; (c) on the average, the coefficients of variation of individual plasma concentrations were lower after the capsule; and (d) for the capsule, the intrasubject variations of the peak plasma concentrations, time of peak, area under plasma concentrations-versus-time curve (AUC), and amount digoxin excreted in urine (Ae) were on the average 60 per cent of the variations in the tablet parameters. The ratios of AUC and Ae for capsule/tablet were essentially unity, indicating that the amount digoxin absorbed from the 0.4-mg digoxin SEG capsule is identical to that from a 0.5-mg standard reference tablet.

Absorption↗
PubMedDate not supplied

A steady-state evaluation of the effects of propantheline bromide and cholestyramine on the bioavailability of digoxin when administered as tablets or capsules.

Drug interactions can profoundly alter the absorption of digoxin in tablet form. This study evaluated whether digoxin solution in capsules, a new dosage form with 90% to 100% bioavailability, would reduce such alterations, specifically those caused by cholestyramine and propantheline bromide. The investigation used a six-treatment, steady-state, balanced, incomplete block design with 18 healthy adults studied for four continuous two-week treatment periods. Treatments were either two 0.25 mg digoxin tablets or two 0.20 mg digoxin capsules administered alone, with propantheline, 15 mg qid, or with cholestyramine, 8 g qd. Bioavailability was determined from steady-state, 24-hour area under the serum concentration-time curve (AUC, ng X h/mL) and from 0- and 24-hour trough serum digoxin concentrations (ng/mL). The AUCs for tablets alone, with cholestyramine, and with propantheline were 32.8 +/- 13.3 (+/- SD), 22.4 +/- 12.1, and 40.6 +/- 13.9, respectively, while corresponding values for capsules were 31.7 +/- 9.3, 24.7 +/- 7.9, and 35.9 +/- 12.8. The trough concentrations for tablets alone, with cholestyramine, and with propantheline were 0.88 +/- 0.47, 0.61 +/- 0.38, and 1.09 +/- 0.35, respectively; trough concentrations for capsules were 0.77 +/- 0.28, 0.74 +/- 0.28, and 0.96 +/- 0.48, respectively. The only significant differences in AUC were seen when comparing tablets alone versus tablets with cholestyramine (P less than .0005) and tablets with propantheline (P less than .01). A significant finding was also observed when comparing trough concentrations for tablets alone versus tablets with cholestyramine (P less than .005).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Digoxin levels in prehospital sudden-death syndrome.

Digitalis toxicity is common and has been associated with ventricular dysrhythmias. Digoxin levels in patients who suffer prehospital sudden death have never been studied. This study measured digoxin levels in a population of sudden-death patients. During the 15-week study period, 252 patients in cardiac arrest were seen by an urban paramedic system. During daytime hours, paramedics were requested to obtain a blood sample from sudden-death patients; the samples were subsequently analyzed for digoxin by means of radioimmunoassay. Thirty-nine patients had measured digoxin levels drawn; 28 (71.8%) were in the therapeutic range (0.5-2.1 ng/mL), and four (10.2%) were in the toxic range (greater than 2.1 ng/mL). The patients with toxic dogoxin levels and those with nontoxic levels had similar resuscitation rates (50.0% vs. 34.3%, P = NS), but none were found in ventricular fibrillation. Emergency medical services personnel should consider digoxin toxicity as a potential etiology of arrest.

Aged↗
PubMed1987

The effect of dietary fiber on the bioavailability of digoxin in capsules.

Sixteen healthy volunteers were regularly given 0.4 mg of digoxin daily as two capsules with breakfast. After ten days during which breakfast was supplemented with 11 g of bran fiber, steady-state predose mean serum digoxin was lower (0.89 +/- 0.19 versus 0.84 +/- 0.18 ng/mL, P less than .05) and mean 24-hour area under curve determination was lower (30.5 +/- 6.1 versus 28.4 +/- 6.0 ng X hr/mL, P less than .05) than during the control period without bran. Height and time of peak serum digoxin, and 24-hour urinary digoxin were not significantly different. The 6 to 7% reduction in digoxin absorption from capsules is less than that reported from tablets and is probably clinically unimportant.

Adult↗
PubMed1996

The effects of epoprostenol on drug disposition. I: A pilot study of the pharmacokinetics of digoxin with and without epoprostenol in patients with congestive heart failure.

The influence of epoprostenol on the pharmacokinetics of drugs administered concurrently to patients with congestive heart failure (CHF) receiving epoprostenol was evaluated as a secondary objective of a Phase II pilot study. A total of 278 blood samples were collected from 30 patients with end-stage CHF receiving conventional therapy alone or conventional therapy plus epoprostenol. Estimates of oral clearance (Cl), volume of distribution, and absorption rate constant of digoxin were generated from plasma digoxin concentrations using nonlinear mixed effects modeling, and the effect of epoprostenol on Cl of digoxin was evaluated by univariate analysis. Additional factors that were evaluated by univariate analysis included age, obesity, time since study entry, cardiac output, concomitant use of angiotensin-converting enzyme (ACE) inhibitor, concomitant dobutamine, and estimated creatinine clearance. Backward elimination was used to arrive at a final model that included concomitant epoprostenol as a covariate. The final model revealed an approximate 15% decrease in Cl of digoxin in response to short-term administration of epoprostenol that was no longer apparent by the end of the 12-week treatment phase. Simulations revealed that this effect, although statistically significant, would not be clinically significant in most patients; however, the potential exists for short-term elevation of digoxin concentrations in response to concurrent administration of epoprostenol.

Adult↗
PubMed1998

Impairment of absorption of digoxin by acarbose.

This study was conducted to determine the effect of acarbose on serum concentrations of digoxin in healthy male volunteers. A randomized crossover design with three phases was used. In phase 1 participants received 0.5 mg of digoxin alone. In phase 2 they received 0.5 mg of digoxin 0.5 hours after a 200-mg dose of acarbose. In phase 3 they received 100 mg of acarbose 0.5 hours before each meal three times daily for 3 days. On the fourth day, they received 0.5 mg of digoxin 0.5 hours after a 100-mg dose of acarbose. Area under the concentration-time curve (AUC0-48) and mean maximum concentration (Cmax) were significantly lower and tmax significantly increased in phases 2 and 3 compared with phase 1. These results indicate that the absorption of digoxin is reduced by administration of acarbose, and that one of the major mechanisms of this interaction may be due to the pharmacodynamics of acarbose.

Absorption↗
PubMed1988

A comparative trial of digoxin and digitoxin in the treatment of congestive heart failure.

A randomized, crossover, single-blind study compared the efficacy and dosing accuracy of digoxin and digitoxin in 15 ambulatory patients wth congestive heart failure. Loading doses and maintenance doses were calculated according to published equations that adjust for sex, height, and lean body weight (for digitoxin), plus estimated creatinine clearance (for digoxin). At each 2-week visit, serum drug concentrations were measured and compliance with the prescribed regimen was assessed by tablet count. At the end of each study period, a congestive heart failure (CHF) score was determined in a blinded fashion by the same physician. Patient compliance was unusually high (greater than or equal to 80%) at every visit. Therapeutic concentrations were achieved with digoxin and digitoxin in 5 and 14 patients, respectively (p less than 0.05). During digitoxin therapy, CHF scores were lower than pretreatment values (p less than 0.05). The difference between CHF scores during the digoxin and digitoxin periods did not achieve significance (0.05 less than p less than 0.06). Therapeutic serum concentrations can be achieved more easily and frequently with digitoxin than digoxin without compromising the patient's CHF status.

Adult↗
PubMed2003

Role of P-glycoprotein in pharmacokinetics and drug interactions of digoxin and beta-methyldigoxin in rats.

Digoxin and beta-methyldigoxin were evaluated pharmacokinetically in terms of P-glycoprotein (P-gp)-mediated drug interactions in rats. Evaluation was made by measuring the effects of a potent P-gp inhibitor (verapamil, cyclosporin A) on in vitro efflux transport of these compounds across the everted small intestine, on in situ absorption from the small intestine, and on in vivo total plasma clearance (CL(total)) as well as biliary and urinary excretions after intravenous administration. Both the intestinal efflux transport and absorption of beta-methyldigoxin were approximately 1.5-fold greater than those of digoxin, probably due to its higher lipophilicity. Addition of verapamil (300 microM) significantly decreased the intestinal efflux transport and increased the intestinal absorption of digoxin. In contrast, the influence of verapamil on beta-methyldigoxin was small. Intravenous cyclosporin A (30 mg/kg) significantly decreased in vivo CL(total) and biliary excretion of digoxin, but affected little on beta-methyldigoxin clearances. These results suggest that P-gp-mediated drug interactions can easily occur in digoxin, but hardly in beta-methyldigoxin. These findings may give a clue in selecting these digitalis compounds in clinical use, towards escape from P-gp-mediated drug interactions or reduction of interindividual variations.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1977

Bioavailability of digoxin in a new soluble pharmaceutical formulation in capsules.

The in vitro dissolution and the bioavailability of two pharmaceutical formulations of digoxin were compared, one being a common commercial tablet form and the other a solution of the glycoside in soft gelatin capsules. Digoxin capsules dissolved more readily in vitro and showed higher bioavailability than digoxin tablets in both dogs and humans. In dogs, the capsules and tablets were compared with an elixir of digoxin, which possesses complete bioavailability. The better bioavailability of digoxin capsules as compared with tablets may be explained by the fact that this formulation contains the cardiac glycoside in a solution.

Adult↗
PubMed1977

Physiologically based pharmacokinetic model for digoxin distribution and elimination in the rat.

A plasma flow rate-limited pharmacokinetic model was developed to describe the distribution of digoxin to the heart, liver, kidneys, skeletal muscle, and GI tract in the rat. The model also provides for renal, hepatic (metabolic and biliary), and GI clearance as well as for biliary and GI secretion and GI reabsorption of digoxin. Predicted concentrations of digoxin in the heart, liver, skeletal muscle, and plasma were consistent with experimental observations in conscious rats after an intravenous dose. The model was extended to describe digoxin concentrations in the plasma of bile duct-ligated rats and ureter-ligated rats, simply by modifying appropriate clearance parameters. Excellent agreement was obtained between predicted and observed urinary excretion rates of digoxin for 12 hr after in intravenous dose to normal and bile duct-ligated rats.

Animals↗
PubMed1978

Kinetics of digoxin stability in aqueous solution.

Digoxin hydrolysis was studied as a function of pH. Conversion of digoxin to digoxigenin was followed by high-pressure liquid chromatography and shown to proceed by the initial loss of one, two, or three sugars. The hydrolysis rate was directly proportional to parent drug concentration and hydrogen-ion activity. The individual hydrolysis rate constants of digoxin, digoxigenin bisdigitoxoside, and digoxigenin monodigitoxoside were determined by a simplex fitting procedure. Data are presented suggesting that at least some variation in the bioavailability of orally administered digoxin arises from observed variations in gastric pH; these variations influence the extent to which hydrolysis occurs and, thus, modify the composition of digoxin species available for absorption.

Chemical Phenomena↗
PubMed1978

Instability of digoxin in acid medium using a nonisotopic method.

A selective nonisotopic assay was used to investigate the digoxin hydrolysis rates at 37 +/- 0.1 degrees over the pH 1.1--2.2 range. The colorimetric method adopted is based on the use of a xanthydrol reagent after extraction with chloroform. The spectrofluorometric method specified in the dissolution test for digoxin tablets was nonspecific because of digoxigenin interference. Digoxin hydrolysis followed specific acid hydrolysis, and K values of the apparent first-order reaction varied from 0.0357 to 0.0027 min-1 over the pH range used. The effect of the dissolution medium on digoxin stability during the dissolution tests of the tablets also was studied. Water (the BP medium) and 0.6% HCl (the USP medium) were compared using the fluorometric method and the xanthydrol method. In the USP medium (pH 1.3), no hydrolysis was revealed by the fluorometric estimation whereas the xanthydrol method showed about 74% hydrolysis. In water, the two methods revealed no hydrolysis. The extent of hydrolysis after 1 hr in the USP medium was studied using three brands of digoxin tablets of differing dissolution characteristics. The fast dissolving brand showed relatively more hydrolysis than the slow dissolving tablets.

Chemistry, Pharmaceutical↗
PubMed1978

Influence of kaolin--pectin suspension on digoxin bioavailability.

The effect of a kaolin--pectin suspension on the bioavailability of orally administered digoxin was evaluated when both drugs were given concomitantly and when their time of administration was separated by 2 hr. Coadministration of the antidiarrheal with the cardiac glycoside delayed absorption of the latter and, at the same time, decreased by 62% the amount of drug absorbed. Intersubject variation in digoxin bioavailability also was increased more than twofold. When the kaolin--pectin suspension was given 2 hr before the cardiac glycoside, the digoxin absorption rate was not affected, although its relative extent of absorption was reduced by about 20%. In contrast, when the antidiarrheal was given 2 hr after digoxin, neither the rate nor the extent of absorption of the cardiac glycoside was perturbed. No change in the intersubject variability in digoxin bioavailability was noted whether the antidiarrheal was given 2 hr before or 2 hr after the cardiac glycoside.

Adult↗
PubMed1979

Bioavailability and related heart function index of digoxin capsules and tablets in cardiac patients.

A loading dose of digoxin (750 microgram) in two commercial formulations was administered to 14 patients with heart disease according to a crossover design. One formulation consisted of soft gelatin capsules containing a solution of digoxin; the other formulation was compressed tablets. All parameters investigated, i.e., serum peak height, time of the peak, area under the serum level--time curve (AUC), and area above the Q--S2I (electromechanical systole) decrease (obtained from polycardiographic evaluation), showed better bioavailability of digoxin capsules than tablets, averaging 36.3%. The better bioavailability of digoxin capsules than tablets seems to be more evident in heart disease patients than that encountered previously in healthy subjects. The AUC and the area above the Q-S2I decrease were linearly correlated only with digoxin capsules.

Adult↗
PubMed1984

Bioavailability of digoxin capsules and tablets: effect of coadministered fluid volume.

The effect of different coadministered fluid (water) volumes on the consistency of digoxin absorption was studied in 16 male volunteers. Each volunteer received four single-dose treatments (two 0.25-mg digoxin tablets with 30- and 240-mL of water and two 0.2-mg digoxin capsules with 30- and 240-mL of water). Digoxin present in serum and urine samples collected for 48 h after dosing was quantified by RIA. Treatments were compared by evaluating the following model-independent pharmacokinetic parameters: maximum serum concentration (Cmax); time of maximum serum concentration (tmax); area under the serum concentration-time curve for 0-12 h (AUC0-12); cumulative urinary excretion for 0-48 h (CUE48). No significant differences were found between dosage form (tablets versus capsules) and coadministered water volume (30 mL versus 240 mL) for any of the parameters. For both fluid volumes the AUC0-12 and Cmax were significantly larger (p less than 0.01) and the tmax significantly shorter (p less than 0.01) for the capsules than for the tablets. The volume of coadministered water had no effect on the amount of digoxin absorbed from either dosage form.

Adult↗
PubMed1994

Contribution of a single heavy chain residue to specificity of an anti-digoxin monoclonal antibody.

Two distinct spontaneous variants of the murine anti-digoxin hybridoma 26-10 were isolated by fluorescence-activated cell sorting for reduced affinity of surface antibody for antigen. Nucleotide and partial amino acid sequencing of the variant antibody variable regions revealed that 1 variant had a single amino acid substitution: Lys for Asn at heavy chain position 35. The second variant antibody had 2 heavy chain substitutions: Tyr for Asn at position 35, and Met for Arg at position 38. Mutagenesis experiments confirmed that the position 35 substitutions were solely responsible for the markedly reduced affinity of both variant antibodies. Several mutants with more conservative position 35 substitutions were engineered to ascertain the contribution of Asn 35 to the binding of digoxin to antibody 26-10. Replacement of Asn with Gln reduced affinity for digoxin 10-fold relative to the wild-type antibody, but maintained wild-type fine specificity for cardiac glycoside analogues. All other substitutions (Val, Thr, Leu, Ala, and Asp) reduced affinity by at least 90-fold and caused distinct shifts in fine specificity. The Ala mutant demonstrated greatly increased relative affinities for 16-acetylated haptens and haptens with a saturated lactone. The X-ray crystal structure of the 26-10 Fab in complex with digoxin (Jeffrey PD et al., 1993, Proc Natl Acad Sci USA 90:10310-10314) reveals that the position 35 Asn contacts hapten and forms hydrogen bonds with 2 other contact residues. The reductions in affinity of the position 35 mutants for digoxin are greater than expected based upon the small hapten contact area provided by the wild-type Asn. We therefore performed molecular modeling experiments which suggested that substitution of Gln or Asp can maintain these hydrogen bonds whereas the other substituted side chains cannot. The altered binding of the Asp mutant may be due to the introduction of a negative charge. The similarities in binding of the wild-type and Gln-mutant antibodies, however, suggest that these hydrogen bonds are important for maintaining the architecture of the binding site and therefore the affinity and specificity of this antibody. The Ala mutant eliminates the wild-type hydrogen bonding, and molecular modeling suggests that the reduced side-chain volume also provides space that can accommodate a congener with a 16-acetyl group or saturated lactone, accounting for the altered fine specificity of this antibody.

Amino Acid Sequence↗
PubMed2002

Digoxin up-regulates MDR1 in human colon carcinoma Caco-2 cells.

Because MDR1 (P-glycoprotein) plays an important role in pharmacokinetics such as absorption and excretion of xenobiotics and multidrug resistance, an understanding of the factors regulating its function and expression is important. Here, the effects of digoxin on cell sensitivity to an anticancer drug, MDR1 function, and expression were examined by assessing the growth inhibition by paclitaxel, the transport characteristics of the MDR1 substrate Rhodamine123, and the level of MDR1 mRNA, respectively, using human colon carcinoma Caco-2 cells, which are widely used as a model of intestinal epithelial cells. The sensitivity to paclitaxel, an MDR1 substrate, in Caco-2 cells pretreated with digoxin was lower than that in non-treated cells. The accumulation of Rhodamine123 was reduced by pretreatment with digoxin and its efflux was enhanced. The level of MDR1 mRNA in Caco-2 cells was increased in a digoxin concentration-dependent manner. These results taken together suggested that digoxin up-regulates MDR1 in Caco-2 cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1989

How to digitalize and to maintain optimal digoxin levels in congestive heart failure.

Due to the narrow therapeutic-to-toxic ratio of digoxin, numerous studies have been done to assess the optimal digoxin level in patients with congestive heart failure. A digoxin level of 0.7-1.5 ng/mL (or 0.9-2.0 nMol/L) is generally considered optimal, but even at these levels toxicity may occur in certain clinical situations such as severe pulmonary disease or when electrolyte or metabolic disturbances are present. The optimal daily maintenance dose of digoxin depends on the preparation given and can be calculated by the equation of Jelliffe, which is largely based on the creatinine clearance of the patient. The daily digoxin dose must also be adjusted to take into consideration disease processes or concomitant drug therapy that can alter the volume of distribution, the biotransformation, or the excretion of the drug.

Digoxin↗