Binding of digitoxin and some related cardenolides to human plasma proteins

Lukas, Daniel S.; Martino, Anthony G. De

doi:10.1172/jci106060

Cited by 136 publications

(44 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We have previously reported a mean value of 97.3% (SD 0.4) in an adult control group (41), a value in good accordance with the 97 % reported by Lukas and deMartino (24).…”

Section: Laboratory Methodssupporting

confidence: 89%

Studies on digitalis. 23. Blood‐brain barrier of digitoxin in humans

Storstein¹,

Nore²,

Sjaastad³

1979

Clinical Cardiology

View full text Add to dashboard Cite

Summary: Data on the cerebrospinal fluid concentrations of digitoxin in man have been lacking. Aim of the present study was to investigate serum and cerebrospinal fluid concentrations of digitoxin. Eleven patients with normal cerebrospinal fluid composition, normal serum albumin values, normal renal and hepatic function and normal hematologic tests were given a single dose of 0.6 mg digitoxin. Serum and cerebrospinal fluid were collected 16 h after the dose, and assayed by radio-immunoassay, serum digitoxin protein binding was measured with equilibrium dialysis.Mean serum digitoxin concentration was 12.4 ng/ml (SO 2.6) and mean CSF concentration 0.84 ngiml (SO 0.22) giving a CSF/serum ratio of 0.07 (SO 0.03). Serum digitoxin protein binding was 97.4% (SO 0.4) and the calculated CSF/free serum digitoxin ratio was thus 2.94 (SO 1.43).Free serum digitoxin concentrations are more relevant for pharmacologic effect than total serum digitoxin concentrations and also for passage into the central nervous system. Using free drug concentrations the ratio between digitoxin in serum and CSF is lower than reported values for digoxin indicating a higher penetrance of digitoxin into the central nervous system. This corresponds well with the higher lipid solubility of digitoxin. Post mortem studies have shown that concentrations are higher in cerebral tissue than in CSF for digoxin. Determination of CSF concentrations thus probably underestimates the penetrance of digitalis glycosides into the central nervous system, but may serve as a useful indicator of variance among digitalis glycosides.

show abstract

“…We have previously reported a mean value of 97.3% (SD 0.4) in an adult control group (41), a value in good accordance with the 97 % reported by Lukas and deMartino (24).…”

Section: Laboratory Methodssupporting

confidence: 89%

Studies on digitalis. 23. Blood‐brain barrier of digitoxin in humans

Storstein¹,

Nore²,

Sjaastad³

1979

Clinical Cardiology

View full text Add to dashboard Cite

show abstract

“…The rapid second-order association kinetics ensure that the free fraction of serum digitoxin concentration will fall to less than 1 nM within a few seconds of the infusion of antibody in the amount used in the experiments reported here, assuming rapid mixing in the intravascular compartment. This rapid binding of digitoxin by antibody occurs in spite of extensive serum albumin binding of digitoxin (14) because of the very rapid dissociation rate of the digitoxin-albumin complex. It should be noted that the degree of digitoxin crossreactivity noted in the present studies cannot be expected for every digoxin-binding antibody population (23).…”

Section: Resultsmentioning

confidence: 99%

“…Lukas and DeMartino demonstrated that 97% of digitoxin at usual therapeutic concentrations is bound to serum albumin (14). An effective approach to the specific treatment of advanced digitoxin intoxication, then, ideally should enhance excretion ofthe drug as well as neutralize its effects before excretion.…”

Section: Resultsmentioning

confidence: 99%

“…Substantial differences exist in plasma protein binding and pharmacokinetics of digitoxin compared with shorter-acting glycosides (13,14). The apolar nature of the digitoxin molecule results in a high degree of binding to serum albumin and presumably accounts as well for substantially higher myocardial tissue to medium glycoside concentration ratios compared with digoxin or ouabain in in vitro studies (15,16).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Reversal of Advanced Digitoxin Toxicity and Modification of Pharmacokinetics by Specific Antibodies and Fab Fragments

Ochs¹,

Smith²

1977

J. Clin. Invest.

View full text Add to dashboard Cite

A B S T R A C T The effects of Fab fragments of highaffinity specific antibodies have been studied in a canine experimental model of lethal digitoxin toxicity. Selected antiserum from sheep immunized and boosted with a digoxin-serum albumin conjugate contained antibodies that cross-reacted with digitoxin with an average intrinsic association constant of 1.4 x 10"0 M-1 as determined by equilibrium dialysis.Rapid second-order association kinetics (kf = 3.7x 106 M-1 per s) and slow dissociation kinetics (kr = 1.9 X 10-4 per s) were documented for the antibody-digitoxin complex. Eight dogs given 0.5 mg/ kg digitoxin intravenously developed ventricular tachycardia after 23±4 (SEM) min. Control nonspecific Fab fragments were then given. All animals died an average of 101+36 min after digitoxin administration. Another eight dogs given the same digitoxin dose similarly developed ventricular tachycardia after 28+3 min. This group then received a molar equivalent dose of specific Fab fragments intravenously over 3 min, followed by a 30-min infusion of one-third of the initial dose. All dogs survived. Conducted sinus beats reappeared 18+4 min after initial Fab infusion, and stable normal sinus rhythm was present at 54 ± 16 min. Plasma total digitoxin concentrations increased threefold during the hour after initial Fab infusion, while plasma free digitoxin concentration decreased to less than 0.1 ng/ml. Effects on digitoxin pharmacokinetics of these Fab fragments and the antibody population from which they were derived were further investigated in a primate species. Unlike common laboratory animals previously studied, the rhesus monkey was found to have a prolonged elimination half-life, estimated at 135Dr. Ochs was a Fellow of Deutsche Forschungsgemeinschaft.Received for publication 20 January 1977 and in revised form 5 July 1977. and 118 h by radioimmunoassay and [3H]digitoxin measurements, respectively, similar to man and thus providing a clinically relevant experimental model. Intravenous administration of 2 mol of specific Fab fragments per mole of digitoxin 6 h after 0.2 mg of digitoxin produced a rapid 4.3-fold increase in plasma total digitoxin concentration followed by a rapid fall (t1 4 h) accompanied by a 14-fold enhancement of urinary digitoxin excretion over control values during the 6-h period after Fab was given. Analytical studies were consistent with increased excretion of native digitoxin rather than metabolites, and the glycoside was found in equilibrium dialysis studies to be excreted in the urine in Fab-bound form. Administration of 2 mol of specific antibody binding sites per mole of digitoxin as intact IgG caused a greater and more prolonged increase in plasma total digitoxin concentration, peaking 13-fold above control levels. In contrast to the effects of Fab, however, specific IgG reduced the rate of urinary digitoxin excretion substantially below control values. We conclude that Fab fragments of antibodies with high affinity for digitoxin are capable of rapid reversal of advanced, otherwise let...

show abstract

“…The binding of both "digoxin-like immunoreactive factors" and digoxin to protein is markedly temperature-dependent (34,39). At 37 °C, 20-25% of digoxin is bound to plasma proteins, but only about 5% is bound at 4 °C.…”

Section: Discussionmentioning

confidence: 99%

Determination of Digoxin in the Blood of Pregnant Women, Fetuses and Neonates before and during Anti-arrhythmic Therapy, Using Four Immunochemical Methods

Schlebusch

Mende²

1991

Clinical Chemistry and Laboratory Medicine

View full text Add to dashboard Cite

Summary:Four immunochemical methods for digoxin assay were used to analyse control samples, 33 amniotic fluid samples, 57 samples from digitalis-treated, non-pregnant women, 90 pregnancy serum samples, and 72 samples of fetal or neonatal serum with or without digoxin therapy. One hundred and five samples were also submitted to ultrafiltration before analysis.Three methods (RIA, TD X , AMERLITE) showed practically the same precision, while the precision of the DELFIA was markedly inferior. In the analysis of serum samples from digoxin-treated, non-pregnant women, RIA and TD X gave practically the same values, whereas AMERLITE and DELFIA gave significantly higher values.Pregnancy serum and fetal serum contain "digoxin-like immunoreactive factors", and the qualitative and quantitative effects of these interfering factors are different for each of the four methods. The greatest sensitivity to "digoxin-like immunoreactive factors" is shown by TD X and DELFIA, while the lowest interference by "digoxin-like immunoreactive factors" is found in the analysis of ultrafiltered samples, using the TD X method.The composition of the "digoxin-like immunoreactive factors" in pregnancy serum and in fetal serum is altered by digoxin therapy, and these changes have different effects on the various analytical methods. The concentration of "digoxin-like immunoreactive factors" in the serum of fetuses receiving digoxin is markedly lower than that of healthy fetuses.For the reliable monitoring of digoxin therapy in the maternal and fetal circulation, the blood samples must be submitted to ültrafiltration before analysis.

show abstract

Binding of digitoxin and some related cardenolides to human plasma proteins

Cited by 136 publications

References 38 publications

Studies on digitalis. 23. Blood‐brain barrier of digitoxin in humans

Studies on digitalis. 23. Blood‐brain barrier of digitoxin in humans

Reversal of Advanced Digitoxin Toxicity and Modification of Pharmacokinetics by Specific Antibodies and Fab Fragments

Determination of Digoxin in the Blood of Pregnant Women, Fetuses and Neonates before and during Anti-arrhythmic Therapy, Using Four Immunochemical Methods

Contact Info

Product

Resources

About