The effect of digoxin-specific active immunization on digoxin toxicity and distribution in the guinea-pig

In guinea-pigs intravenously infused with digoxin, prior immunization using a digoxin-human serum albumin conjugate increased by 3- and 2.4-fold, respectively, the digoxin doses causing the first signs of cardiotoxicity and death. At death, serum digoxin concentration was four times higher in immunized than in control animals. In the immunized guinea-pigs 50% of the serum digoxin was protein bound, presumably mainly to digoxin-specific antibodies, since in the controls the bound fraction was only 1-2%. Generally, tissue digoxin concentrations were not increased to the same extent as the lethal dose, and in the heart and lungs the increase was not significant. With cardiac (ventricle) subcellular fractions, there was no difference between control and immunized animals in the digoxin concentration of the 'microsomal' pellet. This subfraction contains the plasma membrane and the associated sodium pumps which are considered to be the sites at which the pharmacologically active digoxin binds. It seems likely, therefore, that the greater digoxin resistance in the immunized animals can be explained on the basis of reduced drug access to the site of action within the heart.