The plasma kinetics of digoxin-specific Fab fragments and digoxin in the rabbit

Abstract

The plasma kinetics of total and free digoxin, and digoxin-specific antibody fragments (DSFab) in rabbits which had been given [3H]digoxin one hour before DSFab has been studied over a 5 day period. Injection of DSFab caused a 4- to 5-fold rise in total digoxin and reduced elimination half-life (t1/2 beta), apparent volume of distribution at steady-state (Vdss) and systemic clearance (CL) by 40, 90 and 75% respectively. Early in the experimental period, DSFab reduced free digoxin concentration (measured by ultrafiltration) from 4.1 ng mL-1 to a minimum of 1.3 ng mL-1 at 15 min. However, the concentration had rebound to 2.5 ng mL-1 by 60 min. Subsequently, free digoxin fell to 0.63 ng mL-1 and remained relatively constant over a 7 to 90 h period. The distribution half-life, t1/2 beta, Vdss and CL for DSFab (concentrations measured by enzyme-linked immunosorbent assay) were 0.3 h, 3.2 h, 185 mL kg-1 and 57 mL kg-1 h-1, respectively. A considerable molar excess (about 5) of DSFab in the plasma was necessary to maintain minimum free digoxin concentrations. When the DSFab:digoxin molar ratio was less than 4 during the initial treatment period, free (toxicologically active) concentrations increased. With the elevation in total digoxin, however, an opposite situation appeared to apply. By 24 h the relatively short DSFab t1/2 beta meant that the plasma DSFab concentration was less than 0.05 micrograms mL-1 giving a DSFab:digoxin molar ratio of below 0.06, yet the antibody-induced rise in total digoxin concentration was still detectable at 100 h.