Kinetics of Partitioning and Binding of Digoxin and Its Analogues in the Subcompartments of Blood

• Published in: Journal of pharmaceutical sciences 1984-08, Vol.73 (8), p.1042-1053
• Main Author: Hinderling, Peter H.
• Format: Article
• Language: English
• Subjects: Albumins - metabolism; analogues; Biological and medical sciences; Blood Proteins - metabolism; Cardiotonic agents; Cardiovascular system; Digoxin - analogs & derivatives; Digoxin - blood; Digoxin-kinetics of red blood cell partitioning; Digoxin—kinetics of red blood cell partitioning, plasma protein binding, analogues; Erythrocytes - metabolism; Hemoglobins - metabolism; Humans; In Vitro Techniques; Kinetics; kinetics of red blood cell partitioning; Kinetics-digoxin and analogues in blood; Kinetics—digoxin and analogues in blood, plasma protein binding, red blood cell partitioning; Medical sciences; Models, Biological; Pharmacology. Drug treatments; plasma protein binding; Plasma protein binding-digoxin and analogues; Plasma protein binding—digoxin and analogues, kinetics of red blood cell partitioning; Protein Binding; red blood cell partitioning; Red blood cell partitioning-digoxin and analogues; Red blood cell partitioning—digoxin and analogues, kinetics, plasma protein binding; Temperature
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.2600730807

The kinetics of digoxin and analogues (metabolites) in the sub-compartments of blood, erythrocytes and plasma, were first order and concentration independent. The rate and extent of red blood cell partitioning of the tested compounds were, according to first-order kinetics, identical in the presence and absence of structurally related compounds and dependent on lipophilicity and temperature; red blood cell penetration was a reversible process. Erythrocyte partitioning of digoxin and its analogues was postulated to be by passive diffusion. There was significant intracellular binding of the compounds, and hemoglobin was the major ligand. The kinetics of red blood cell partitioning of the individual compounds were fitted according to a closed two- or three-compartment model. The latter indicated the existence of two kinetically separable compartments within the red blood cells. Model-independent mean transit times of red blood cell-plasma water partitioning of the compounds depended largely on the lipophilicity and were a thousand times greater for the least lipophilic analogues than for the most lipophilic derivatives. Red blood cell partitioning of digoxin and its metabolites under in vivo and in vitro conditions, were equivalent. Plasma protein binding of the tested compounds was concentration independent, unaltered in the presence of the analogues, and temperature independent between 24°C and 37°C. Binding to albumin in buffer solution was significantly larger than to albumin in plasma for all the compounds. Binding of digoxin and its analogues to albumin in buffer solution increased with increasing lipophilicity of the compounds.