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Analytical Chemistry Feb 2015This study focuses on the quantitative analysis of the cardiac glycoside drug digitoxin and its three main metabolites digitoxigenin-bisdigitoxose,...
This study focuses on the quantitative analysis of the cardiac glycoside drug digitoxin and its three main metabolites digitoxigenin-bisdigitoxose, digitoxigenin-monodigitoxose, and digitoxigenin using electrospray ionization-differential ion mobility spectrometry-tandem mass spectrometry (ESI-DMS-MS/MS). Despite large molecular weight differences, gas-phase separation of the four compounds in the DMS drift cell was not possible, even by utilizing additional volatile chemical modifiers. Baseline separation was achieved after adduct formation with alkali metal ions, however, and efficiency was shown to improve with increasing size of the alkali ion, reaching optimum conditions for the largest cesium ion. Subsequently, an assay was developed for quantification of digitoxin and its metabolites from human serum samples and its analytical performance assessed in a series of proof-of-concept experiments. The method was applied to spiked human serum pools with concentration levels between 2 and 80 ng/mL. After a short reversed-phase chromatographic step for desalting the sample, rapid DMS separation of the analytes was carried out, resulting in a total run time of less than 1.5 min. The instrumental method showed good repeatability; the calculated coefficients of variation ranged from 2% to 13%.
Topics: Cardiotonic Agents; Digitoxin; Humans; Limit of Detection; Models, Molecular; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry
PubMed: 25588102
DOI: 10.1021/ac503187z -
Clinical Pharmacology and Therapeutics Nov 1984The kinetics of digitoxin and two of its metabolites, the bis- and monodigitoxosides of digitoxigenin, were determined in six normal subjects. Mean t 1/2s and total body... (Comparative Study)
Comparative Study
The kinetics of digitoxin and two of its metabolites, the bis- and monodigitoxosides of digitoxigenin, were determined in six normal subjects. Mean t 1/2s and total body clearances were 134.4, 15.4, and 0.59 hr and 2.66, 27.3, and 1071 ml/min. Mean renal clearance of the monodigitoxoside was more rapid (7.24 ml/min) than those of digitoxin (0.81 ml/min) or the bisdigitoxoside (0.94 ml/min). The volumes of distribution were of the same order, 0.45 l/kg for digitoxin, 0.57 l/kg for the bisdigitoxoside, and 0.83 l/kg for the monodigitoxoside. The short t 1/2 of monodigitoxoside would make it unsuitable for clinical use, but the bisdigitoxoside of digitoxigenin has a t 1/2 of an intermediate length and may have significant therapeutic advantages.
Topics: Adult; Aged; Digitoxigenin; Digitoxin; Drug Evaluation; Female; Half-Life; Humans; Injections, Intravenous; Kinetics; Male; Middle Aged; Radioimmunoassay
PubMed: 6488680
DOI: 10.1038/clpt.1984.228 -
Drug Metabolism and Disposition: the... 1977
Topics: Animals; Biotransformation; Cell-Free System; Digitoxigenin; Digitoxin; Glucuronates; Liver; Male; Rabbits; Rats
PubMed: 20296
DOI: No ID Found -
The Journal of Organic Chemistry Mar 2007A highly enantioselective and straightforward route to trisaccharide natural products digoxose and digitoxin has been developed. Key to this approach is the iterative...
A highly enantioselective and straightforward route to trisaccharide natural products digoxose and digitoxin has been developed. Key to this approach is the iterative application of the palladium-catalyzed glycosylation reaction, reductive 1,3-transposition, diastereoselective dihydroxylation, and regioselective protection. The first total synthesis of natural product digoxose was accomplished in 19 total steps from achiral 2-acylfuran, and digitoxin was fashioned in 15 steps starting from digitoxigenin 2 and pyranone 8beta. This flexible synthetic strategy also allows for the preparation of mono- and disaccharide analogues of digoxose and digitoxin.
Topics: Carbohydrate Conformation; Catalysis; Digitoxin; Disaccharides; Glucose; Glycosylation; Oxygen; Palladium; Stereoisomerism; Trisaccharides
PubMed: 17338573
DOI: 10.1021/jo062534+ -
Clinical Pharmacology and Therapeutics May 1977The metabolic pattern of cardioactive and conjugated digitoxin metabolites was studied in 10 uremic patients on maintenance treatment with digitoxin 24 hr after the last... (Comparative Study)
Comparative Study
The metabolic pattern of cardioactive and conjugated digitoxin metabolites was studied in 10 uremic patients on maintenance treatment with digitoxin 24 hr after the last dose (mean dose, 0.060 mg/day). Urine was collected over 24 hr. The mean serum digitoxin level was 9.4 ng/ml, and urine level was 6.8 ng/ml. The metabolic pattern of cardioactive metabolites was studied in 5 patients on hemodialysis. Their mean serum digitoxin level was 6.3 ng/ml and urine level was 7.3 ng/ml, on a digitoxin dose of 0.072 mg/day. Unchanged digitoxin was the main cardioactive substance present in both serum and urine of uremic patients. Uremic patients had significantly less unchanged digitoxin and had more hydroxylated (DG-3) and hydroxylated and hydrolyzed (DG-2, DG-1, and DG-0) metabolites than control patients. The extent of conjugation was the same in the two groups. Our data suggest that uremic patients produce more digitoxose than control patients and that digitoxin elimination is more rapid in uremic patients. The altered pattern of digitoxin metabolites is most consistent with uremia-induced changes in hydroxylation and hydrolysis. The hemodialysis group had a pattern of digitoxin and cardioactive metabolites similar to control patients, indicating that patients on hemodialysis differ from other uremic patients with respect to digitoxin metabolism.
Topics: Biotransformation; Chromatography, Thin Layer; Digitoxin; Humans; Hydrolysis; Hydroxylation; Kinetics; Radioisotopes; Renal Dialysis; Rubidium; Uremia
PubMed: 858212
DOI: 10.1002/cpt1977215536 -
Journal of Clinical Pharmacology Apr 1979A gas-chromatographic mass-spectroscopic technique was used to identify dihydrodigitoxin, a metabolite of digitoxin, in the plasma of healthy volunteers and patients...
A gas-chromatographic mass-spectroscopic technique was used to identify dihydrodigitoxin, a metabolite of digitoxin, in the plasma of healthy volunteers and patients with renal failure. Digitoxin and dihydrodigitoxin were extracted from plasma and derivatized with heptafluorbutyric anhydride. In normal subjects, only minimal concentrations of dihydrodigitoxin in plasma could be determined (1 ng/ml) after an intravenous bolus injection of digitoxin. Under a chronic treatment with a daily dose of 0.1 mg digitoxin in three out of seven individuals, detectable dihydrodigitoxin plasma levels were observed (0.7, 1.5, and 1.7 ng/ml) (Table I). On the other hand, in seven patients with renal failure, high dihydrodigitoxin plasma concentrations (8.9 +/- 0.9 ng/ml) were shown which were in a similar range as those of the parent compound (8.7 +/- 2.2 ng/ml) under a maintenance treatment with digitoxin.
Topics: Adult; Biotransformation; Digitoxin; Humans; Hydrogenation; Kidney Failure, Chronic
PubMed: 438353
DOI: 10.1002/j.1552-4604.1979.tb01651.x -
The Journal of Organic Chemistry Dec 2013A mild and atom-economic rhenium(V)-catalyzed stereoselective synthesis of β-D-digitoxosides from 6-deoxy-D-allals has been described. This β-selective glycosylation...
A mild and atom-economic rhenium(V)-catalyzed stereoselective synthesis of β-D-digitoxosides from 6-deoxy-D-allals has been described. This β-selective glycosylation was achieved probably because of the formation of corresponding α-digitoxosides disfavored by 1,3-diaxial interaction. In addition, this method has been successfully applied to the synthesis of digitoxin trisaccharide glycal for the direct synthesis of digitoxin and C1'-epi-digitoxin.
Topics: Carbohydrate Conformation; Carbohydrate Sequence; Catalysis; Digitoxin; Molecular Sequence Data; Stereoisomerism
PubMed: 24295510
DOI: 10.1021/jo4021419 -
Lancet (London, England) Nov 1981
Topics: Aged; Charcoal; Digitoxin; Digoxin; Electrocardiography; Female; Humans
PubMed: 6118621
DOI: 10.1016/s0140-6736(81)90632-2 -
Biological & Pharmaceutical Bulletin Apr 1994In order to obtain specific antisera to digitoxin, four new types of hapten-bovine serum albumin (BSA) conjugates were synthesized from digitoxin. The haptens were...
In order to obtain specific antisera to digitoxin, four new types of hapten-bovine serum albumin (BSA) conjugates were synthesized from digitoxin. The haptens were linked to the carrier protein through hemisuccinate and hemisuccinylglycine bridges at the C-3' and C-3" positions in the digitoxose chain. The antisera were prepared by immunizing rabbits with each digitoxin-BSA conjugate and the properties of the antisera were investigated by RIA with 3H-labeled digitoxin. Among these antisera, the antiserum raised against digitoxin 3'-hemisuccinate-BSA conjugate possessed high specificity for digitoxin, exhibiting only minor cross-reactions with digitoxigenin bisdigitoxoside (4.0%), dihydrodigitoxin (2.8%), digoxin (2.4%), digitoxigenin monodigitoxoside (0.23%) and digitoxigenin (< 0.05%).
Topics: Animals; Cattle; Cross Reactions; Cross-Linking Reagents; Digitoxin; Haptens; Hexoses; Immune Sera; Rabbits; Radioimmunoassay; Serum Albumin, Bovine; Spectrometry, Mass, Fast Atom Bombardment
PubMed: 8069249
DOI: 10.1248/bpb.17.467 -
Clinical Pharmacokinetics 1985The pharmacokinetic effect of extracorporeal elimination can be evaluated from the extracorporeal elimination rate constant, from the amount of drug removed, and from...
The pharmacokinetic effect of extracorporeal elimination can be evaluated from the extracorporeal elimination rate constant, from the amount of drug removed, and from extracorporeal clearance. To compare the validity of these approaches in clinical practice, the effect of multiple plasma exchanges on the steady-state kinetics of digoxin (5 patients) and digitoxin (9) was investigated. For digoxin, an unchanged elimination half-life (28 hours) and only slight increase in the total body clearance was found (from 203 to 204 ml/min). There was a more pronounced effect on the kinetics of digitoxin, where the elimination half-life decreased from 4.3 to 3.6 days, and the total body clearance increased from 4.4 to 4.7 ml/min. For digoxin there was no statistically significant difference between observed and predicted steady-state trough plasma concentrations. For digitoxin, the observed trough plasma concentrations at steady-state correlated well (p less than 0.05) with the predicted concentrations calculated from the amount removed or from extracorporeal clearance. The magnitude of the kinetic effect of plasma exchange is overestimated using the extracorporeal elimination rate constant; but the effect of extracorporeal elimination can be adequately evaluated from the amount of drug removed and from extracorporeal clearance. These later approaches can be considered model-independent. Thus, the influence of multiple plasma exchanges on the steady-state kinetics of digoxin and digitoxin will be limited and dosage adjustment is not required, if these drugs are given after - not before - the procedure and hypoalbuminaemia is corrected.
Topics: Adult; Aged; Digitoxin; Digoxin; Female; Half-Life; Humans; Kidney Diseases; Kinetics; Male; Middle Aged; Plasma Exchange
PubMed: 4064450
DOI: 10.2165/00003088-198510060-00004