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Clinical Pharmacology and Therapeutics Apr 1976The disposition of digitoxin was studied for a period of 8 days in 6 uremic patients given a single oral dose of 1 mg 3H-digitoxin. In plasma, the time-course of...
The disposition of digitoxin was studied for a period of 8 days in 6 uremic patients given a single oral dose of 1 mg 3H-digitoxin. In plasma, the time-course of radioactivity indicated a diminished absorption velocity of tritium compared to that of control subjects already reported and, after reaching of a pseudostate-equilibrium at 24 hr, an exponential decline with a mean half-life of 8.0 days. In urine, smaller amounts of tritiated compounds were eliminated in uremic patients (8.7% of the dose) than in controls (22.5%). The average fecal excretion of digitoxin and its metabolites was not significantly increased. Chloroform extraction and thin-layer chromatography in plasma, urine and feces suggested no qualitative alteration in the metabolism of digitoxin. Calculations of the total body tritium content (body stores) after each 24-hr interval and its pharmacokinetic behavior showed that the elimination of digitoxin is determined by the transfer constant from tissue to plasma. The differences in elimination kinetics of digitoxin and its metabolites of uremic patients and healthy subjects were not significant.
Topics: Chromatography, Thin Layer; Digitoxin; Feces; Female; Humans; Kidney Failure, Chronic; Kinetics; Male; Time Factors
PubMed: 1269191
DOI: 10.1002/cpt1976194387 -
The American Journal of Medicine Apr 1975The pharmacokinetics of digoxin and digitoxin in patients undergoing long-term hemodialysis were examined to determine which is the preferred cardiac glycoside in this... (Comparative Study)
Comparative Study
The pharmacokinetics of digoxin and digitoxin in patients undergoing long-term hemodialysis were examined to determine which is the preferred cardiac glycoside in this patient population. Absorption curves from 0 to 24 hours after an oral dose of digitoxin were similar in dialyzed patients and in control patients. Serum glycoside concentrations after an oral dose of digoxin were higher in dialyzed patients than in control patients, significantly so from 2 to 24 hours, reflecting the absence of the predominantly renal route of excretion of digoxin. When nine dialyzed patients were placed on a maintenance dose of digoxin, 0.125 mg 5 days a week, serum levels plateaued at 30 days at a mean concentration (plus or minus SE) of 0.84 plus or minus 0.05 ng/ml. Maintenance therapy with 0.1 mg digitoxin 5 days a week resulted in stabilization of serum levels within 30 days at a mean concentration of 19 plus or minus 1 ng/ml. Variability in the serum glycoside concentrations was determined after stabilization of levels during 2 to 19 week follow-up periods with each drug. Variability in serum levels was somewhat increased during maintenance therapy with digitoxin. On the basis of the parmacokinetic data obtained in this study, no clear cut preference for one glycoside over the other could be established.
Topics: Adult; Digitoxin; Digoxin; Heart Failure; Humans; Kidney Failure, Chronic; Kinetics; Middle Aged; Renal Dialysis
PubMed: 1124790
DOI: 10.1016/0002-9343(75)90126-6 -
Deutsche Medizinische Wochenschrift... Oct 1982
Topics: Adolescent; Adult; Aged; Cholestyramine Resin; Digitoxin; Female; Humans; Kinetics; Middle Aged; Protein Binding; Time Factors
PubMed: 7117163
DOI: 10.1055/s-2008-1070152 -
Archives of Biochemistry and Biophysics Nov 1986The aim of the present study was to investigate whether the mechanism by which pregnenolone-16 alpha-carbonitrile (PCN) protects rats from digitoxin toxicity was...
Digitoxin metabolism by liver microsomal cytochrome P-450 and UDP-glucuronosyltransferase and its role in the protection of rats from digitoxin toxicity by pregnenolone-16 alpha-carbonitrile.
The aim of the present study was to investigate whether the mechanism by which pregnenolone-16 alpha-carbonitrile (PCN) protects rats from digitoxin toxicity was dependent on the induction of liver microsomal cytochrome P-450p and/or the UDP-glucuronosyltransferase active toward digitoxigenin monodigitoxoside (UDP-GT-dt1). Evidence is presented that suggests troleandomycin is a selective inhibitor of cytochrome P-450p in vivo, based on the pattern of inhibition observed when zoxazolamine paralysis time and hexobarbital sleeping time were measured in rats treated with different cytochrome P-450 inducers. A single dose of troleandomycin completely reversed the ability of PCN to protect rats from digitoxin toxicity, establishing the importance of cytochrome P-450p induction in the protective effect of PCN. The postpubertal decline in constitutive cytochrome P-450p levels in female but not male rats was paralleled by a female-specific, age-dependent decline in the rate of digitoxin sugar cleavage (i.e., digitoxosyl oxidation of digitoxin to 15'-dehydrodigitoxin and digitoxosyl cleavage to digitoxigenin bisdigitoxoside). This resulted in a marked sex difference in the rate of digitoxin sugar cleavage catalyzed by liver microsomes from mature rats (male/female approximately 6). However, no sex difference in digitoxin toxicity was observed in either immature or mature rats. In contrast to cytochrome P-450p, liver microsomal UDP-GT-dt1 activity increased dramatically with age in both male and female rats (mature/immature approximately 10). However, no age differences in digitoxin toxicity were observed in rats of either sex. The results indicate that cytochrome P-450p and UDP-GT-dt1 can be independently regulated in rat liver and that large changes in the constitutive levels of these microsomal enzymes have no effect on digitoxin toxicity. This suggests that the induction of cytochrome P-450p and UDP-GT-dt1 does not fully account for the mechanism by which PCN protects rats from digitoxin toxicity.
Topics: Age Factors; Animals; Biotransformation; Cytochrome P-450 Enzyme System; Digitoxin; Female; Glucuronosyltransferase; Male; Microsomes, Liver; Pregnenolone Carbonitrile; Rats; Sex Factors; Troleandomycin
PubMed: 3098175
DOI: 10.1016/0003-9861(86)90065-2 -
The Journal of Clinical Investigation Dec 1971Previous studies have demonstrated that considerable amounts of parenterally administered cardiac glycosides are excreted in the bile and reabsorbed across the...
Previous studies have demonstrated that considerable amounts of parenterally administered cardiac glycosides are excreted in the bile and reabsorbed across the intestinal mucosa in several species. It is currently believed that the more prolonged action of nonpolar digitalis glycosides is due to their retention and recycling in the enterohepatic circulation. This report describes studies carried out to evaluate the effects of pharmacologic interruption of this enterohepatic cycle with the intraluminal sequestering agent cholestyramine. Cholestyramine was found to bind substantial quantities of digitoxin-(3)H and digoxin-(3)H in vitro and this binding was only modestly inhibited by the presence of bile. Administration of cholestyramine to rats by intragastric catheter before the subcutaneous injection of the LD(100) dose of digitoxin (10 mg/kg) resulted in a 70% survival rate. Further, oral administration of cholestyramine to rats before the subcutaneous injection of digitoxin-(3)H resulted in accelerated fecal excretion of radioactivity and lower levels of digitoxin-(3)H and metabolites in brain tissue compared to controls. Similarly, pretreatment of guinea pigs with cholestyramine orally before the injection of digitoxin in dosages of 10.0 and 4.0 mg/kg resulted in a 25 and 70% survival rate respectively as compared to survival rates of 0 and 30% in control animals. Cholestyramine pretreatment of guinea pigs was also accompanied by lower levels of digitoxin-(3)H and metabolites in heart and liver 90 min after injection of digitoxin-(3)H. Cholestyramine therapy did not result in significant changes in serum potassium levels excluding the possibility that drug-induced hyperkalemia might have affected the cardiac uptake of digitoxin. The data obtained in this study indicate that cholestyramine treatment affords a significant degree of protection against lethal digitoxin intoxication in rats and guinea pigs. It is suggested that cholestyramine binds appreciable amounts of digitoxin in the intestinal lumen resulting in reduced reabsorption, increased fecal excretion, and lower tissue levels of glycoside in critical organs. The protective effects of cholestyramine appear to be mediated by interruption of the enterohepatic circulation of digitoxin.
Topics: Administration, Oral; Animals; Bile; Cholestyramine Resin; Chromatography, Thin Layer; Digitoxin; Digoxin; Female; Guinea Pigs; Intestinal Absorption; Liver; Rats; Time Factors; Tritium
PubMed: 5129314
DOI: 10.1172/JCI106763 -
Japanese Heart Journal Sep 1979Serum concentrations of digitoxin and digoxin were measured in 145 cases with various heart diseases receiving maintenance doses of digitalis. Digitalis toxicity was...
Serum concentrations of digitoxin and digoxin were measured in 145 cases with various heart diseases receiving maintenance doses of digitalis. Digitalis toxicity was seen in only 2 cases (1.4%). Day-to-day variation of serum concentration while taking the same daily dose was small in digitoxin therapy (13.8%), but a considerable variation was seen in digoxin therapy (24.4%). Serum concentrations of both digitoxin and digoxin were measured in the patients receiving digitoxin, and there was a positive correlation between the two (r = 0.66, p less than 0.001). This fact suggested that the effect of digitoxin was the sum of the effects of digitoxin and its metabolite, digoxin. In the patients taking digoxin, digitoxin was not detected in the serum. Serum digitoxin level had a significantly positive correlation to serum albumin level, presumably because digitoxin was retained in serum in the bound form to albumin. Minimal effective level, 10 ng/ml, was however obtained with higher daily dose of digitoxin in patients with lower serum albumin.
Topics: Adolescent; Adult; Aged; Digitoxin; Digoxin; Female; Heart Diseases; Humans; Male; Middle Aged; Radioimmunoassay
PubMed: 501928
DOI: 10.1536/ihj.20.623 -
The Journal of Laboratory and Clinical... Apr 1975Derivatives of digoxin and digitoxin were measured by the Na-K-ATPase displacement assay and by radioimmunoassay and the data compared with biological potency of these...
Derivatives of digoxin and digitoxin were measured by the Na-K-ATPase displacement assay and by radioimmunoassay and the data compared with biological potency of these compounds. There was a slightly higher affinity of digoxigenin-bis-digitoxoside as compared with digoxin using digoxin-specific antiserum and considerably less affinity of digoxigenin and dihydrodigoxin than the parent compound in the same system. A similar trend was observed for the derivatives of digitoxin using digoxin-specific antiserum. The recovery on extraction of some of the derivatives of digoxin and digitoxin differed from that of the parent compounds in the ATPase assay. The potency of the derivatives of these drugs in displacing 3H ouabain also differed from the parent compoundmboth the recovery on extraction and the potency for displacing ouabain must be considered in the estimation of the contribution of the derivatives of digoxin or digitoxin to the result of Na-K-ATPase assay. Quantitative information of the metabolites of digoxin and digitoxin in normal and pathological conditions is needed to properly interpret assay data obtained either by radioimmunoassay or by ATPase assay.
Topics: Adenosine Triphosphatases; Animals; Digitalis Glycosides; Digitoxin; Digoxin; Humans; Immune Sera; Ouabain; Potassium; Radioimmunoassay; Sheep; Sodium
PubMed: 123547
DOI: No ID Found -
Proceedings of the Society For... Jun 1947
Topics: Animals; Cardiovascular Agents; Cats; Digitoxin
PubMed: 20250434
DOI: 10.3181/00379727-65-15907 -
Toxicology and Applied Pharmacology Aug 1975
Topics: Animals; Bile; Chromatography, Gel; Chromatography, Thin Layer; Digitoxigenin; Digitoxin; Drug Interactions; Glycosides; In Vitro Techniques; Liver; Male; Probenecid; Rats
PubMed: 1179430
DOI: 10.1016/0041-008x(75)90091-5 -
Organic Letters Sep 2006A convergent and stereocontrolled route to trisaccharide natural product digitoxin has been developed. The route is amenable to the preparation of both the digitoxigen...
A convergent and stereocontrolled route to trisaccharide natural product digitoxin has been developed. The route is amenable to the preparation of both the digitoxigen mono- and bisdigitoxoside. This route featured the iterative application of the palladium-catalyzed glycosylation reaction, reductive 1,3-transposition, diastereoselective dihydroxylation, and regioselective protection. The natural product digitoxin was fashioned in 15 steps starting from digitoxigenin 2 and pyranone 8a or 18 steps from achiral acylfuran.
Topics: Carbohydrate Sequence; Digitoxigenin; Digitoxin; Glycosylation; Molecular Sequence Data; Palladium; Stereoisomerism
PubMed: 16956221
DOI: 10.1021/ol061683b