Spironolactone-associated digoxin radioimmunoassay interference.

Apparent digoxin was measured in the serum of 21 patients receiving spironolactone and in 21 controls, by use of a sequential-saturation 3H-radioimmunoassay (RIA) and an equilibrium 125I-RIA. No patient had been given digoxin for at least four weeks. "Digoxin" values in the former group were significantly (p less than 0.05) higher than in the control group, and often were in or near the "therapeutic" range by the equilibrium 125I-RIA, but not by the sequential-saturation 3H-RIA. Canrenone (a major active metabolite of spironolactone) in the serum of the former group was measured by a newly developed liquid-chromatographic technique and correlated (r = 0.73) with "digoxin" concentrations by the 125I-RIA. However, external addition of canrenone to control serum in comparable concentrations did not cause appreciable "digoxin" values by the 125I-RIA. These findings suggest that other metabolites of spironolactone are responsible for the assay interference, the degree of which appears to depend on antibody specificity. Therefore, assay specificity should be established in clinical laboratories by using digoxin-free serum from patients ingesting spironolactone, and not by using spironolactone- or canrenone-fortified digoxin-free serum.