Subject(s)
Digitoxin/metabolism , Acetates , Acylation , Administration, Oral , Adult , Aged , Anhydrides , Carbon Isotopes , Chromatography, Paper , Digitoxin/administration & dosage , Digitoxin/blood , Digitoxin/toxicity , Digitoxin/urine , Feces/analysis , Female , Half-Life , Heart Rate/drug effects , Humans , Hydroxysteroid Dehydrogenases , Injections, Intramuscular , Kidney/metabolism , Kidney Function Tests , Kinetics , Liver/metabolism , Male , Methods , Middle Aged , Muscles/metabolism , Myocardium/metabolism , Pseudomonas/enzymology , Stereoisomerism , TritiumSubject(s)
Body Fluids , Myocardium , Nitrous Oxide , Solubility , Animals , Autopsy , Blood , Cell Membrane , Chromatography, Gas , Dogs , Erythrocytes , Heart Diseases , Hematocrit , Hemoglobins , Humans , Isotonic Solutions , Sodium Chloride , Tonometry, Ocular , WaterSubject(s)
Cardiac Catheterization/adverse effects , Sepsis/etiology , Adolescent , Adult , Aged , Angiocardiography/adverse effects , Anti-Infective Agents/therapeutic use , Blood/microbiology , Contrast Media/adverse effects , Endocarditis, Bacterial/etiology , Endocarditis, Bacterial/prevention & control , Female , Fever/etiology , Humans , Male , Middle Aged , Sepsis/prevention & controlABSTRACT
Tritium-labeled digitoxin, digitoxigenin, digoxin, and digoxigenin of established purity and chemcal authenticity were used to study the binding of these compounds to human plasma proteins. 97% of digitoxin in plasma was nondialyzable. Continuous flow paper electrophoresis of plasma containing digitoxin and dialysis experiments in which human serum albumin competed for the glycoside with plasma or plasma protein fractions demonstrated that digitoxin was almost exclusively bound by albumin. Equilibrium dialyses revealed that the interaction was characterized by a single binding site on the albumin molecule and an association constant of 9.62 x 10(4) liter/mole at 37 degrees C. At 1 degrees C the association constant was 4.64 x 10(4) liter/mole. The interaction therefore was endothermic; the gain in enthalpy of 3.5 kcal/mole and the free energy change of - 7.06 kcal/mole was derived from a large change in entropy of 33.8 cal/mole per degrees K. The direction of these thermodynamic changes suggested the formation of a hydrophobic bond between digitoxin and albumin. Quenching of the fluorescence of albumin by digitoxin indicated that the conformation of albumin was altered by the binding process.Digitoxigenin, its mono- and didigitoxosides, digoxin, and digoxigenin competed with digitoxn for its binding site on albumin. The affinity of the mono- and didigitoxosides for the site was equal to that of digitoxin, but that of digitoxigenin was only one-third as great. The ability of the digitoxose residues of the glycosides to enhance binding to albumin was also observed with digoxin, which was more extensively bound by the protein than digoxigenin. At concentrations of 2 mug/ml or less in plasma, only 23% of digoxin was bound. Albumin, which interacted with digoxin with an apparent association constant of 9 x 10(2) liter/mole at 37 degrees C, was entirely responsible for the binding. Lowering the temperature from 37 degrees to 1 degrees C decreased the fraction of digoxin bound to albumin by two-thirds. The marked difference in avidity of digitoxin and digoxin for serum albumin is reflected by the higher plasma concentrations, lower rate of urinary excretion, and longer half-time of digitoxin as compared to those of digoxin when these compounds are administered to man.
